Modulators of MALAT1 expression

ABSTRACT

The present embodiments provide methods, compounds, and compositions useful for inhibiting MALAT1 expression, which may be useful for treating, preventing, or ameliorating a cancer associated with MALAT1.

SEQUENCE LISTING

The present application is being filed along with a Sequence Listing inelectronic format. The Sequence Listing is provided as a file entitledBIOL00359USSEQ_ST25.txt created Feb. 20, 2020 which is 596 kb in size.The information in the electronic format of the sequence listing isincorporated herein by reference in its entirety.

FIELD

The present embodiments provide methods, compounds, and compositionsuseful for inhibiting MALAT1 expression, which can be useful fortreating, preventing, or ameliorating a cancer associated with MALAT1.

BACKGROUND

Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is anon-coding lncRNA expressed in many human cell types and is highlyconserved across mammalian species. MALAT1 was initially identified frommetastatic NSCLC patients and is upregulated in multiple types of cancer(Zhang X. et al., RNA Biol. 2017, Ping J et al., 2003).

Certain embodiments provided herein are directed to potent and tolerablecompounds and compositions useful for inhibiting MALAT1 expression,which can be useful for treating, preventing, ameliorating, or slowingprogression of cancer associated with MALAT1.

DETAILED DESCRIPTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the embodiments, as claimed. Herein, the useof the singular includes the plural unless specifically statedotherwise. As used herein, the use of “or” means “and/or” unless statedotherwise. Furthermore, the use of the term “including” as well as otherforms, such as “includes” and “included”, is not limiting.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.All documents, or portions of documents, cited in this application,including, but not limited to, patents, patent applications, articles,books, treatises, and GenBank and NCBI reference sequence records arehereby expressly incorporated by reference for the portions of thedocument discussed herein, as well as in their entirety.

It is understood that the sequence set forth in each SEQ ID NO in theexamples contained herein is independent of any modification to a sugarmoiety, an internucleoside linkage, or a nucleobase. As such, compoundsdefined by a SEQ ID NO may comprise, independently, one or moremodifications to a sugar moiety, an internucleoside linkage, or anucleobase. Compounds described by ION number indicate a combination ofnucleobase sequence, chemical modification, and motif.

Unless otherwise indicated, the following terms have the followingmeanings:

“2′-deoxynucleoside” means a nucleoside comprising 2′-H(H) furanosylsugar moiety, as found in naturally occurring deoxyribonucleic acids(DNA). In certain embodiments, a 2′-deoxynucleoside may comprise amodified nucleobase or may comprise an RNA nucleobase (uracil).

“2′-O-methoxyethyl” (also 2′-MOE and 2′-O(CH₂)₂—OCH₃) refers to anO-methoxy-ethyl modification at the 2′ position of a furanosyl ring. A2′-O-methoxyethyl modified sugar is a modified sugar.

“2′-MOE nucleoside” (also 2′-O-methoxyethyl nucleoside) means anucleoside comprising a 2′-MOE modified sugar moiety.

“2′-substituted nucleoside” or “2-modified nucleoside” means anucleoside comprising a 2′-substituted or 2′-modified sugar moiety. Asused herein, “2′-substituted” or “2-modified” in reference to a sugarmoiety means a sugar moiety comprising at least one 2′-substituent groupother than H or OH.

“3′ target site” refers to the nucleotide of a target nucleic acid whichis complementary to the 3′-most nucleotide of a particular compound.

“5′ target site” refers to the nucleotide of a target nucleic acid whichis complementary to the 5′-most nucleotide of a particular compound.

“5-methylcytosine” means a cytosine with a methyl group attached to the5 position.

“About” means within ±10% of a value. For example, if it is stated, “thecompounds affected about 70% inhibition of MALAT1”, it is implied thatMALAT1 levels are inhibited within a range of 60% and 80%.

“Administration” or “administering” refers to routes of introducing acompound or composition provided herein to an individual to perform itsintended function. An example of a route of administration that can beused includes, but is not limited to parenteral administration, such assubcutaneous, intravenous, or intramuscular injection or infusion.

“Administered concomitantly” or “co-administration” means administrationof two or more compounds in any manner in which the pharmacologicaleffects of both are manifest in the patient. Concomitant administrationdoes not require that both compounds be administered in a singlepharmaceutical composition, in the same dosage form, by the same routeof administration, or at the same time. The effects of both compoundsneed not manifest themselves at the same time. The effects need only beoverlapping for a period of time and need not be coextensive.Concomitant administration or co-administration encompassesadministration in parallel or sequentially.

“Amelioration” refers to an improvement or lessening of at least oneindicator, sign, or symptom of an associated disease, disorder, orcondition. In certain embodiments, amelioration includes a delay orslowing in the progression or severity of one or more indicators of acondition or disease. The progression or severity of indicators may bedetermined by subjective or objective measures, which are known to thoseskilled in the art.

“Animal” refers to a human or non-human animal, including, but notlimited to, mice, rats, rabbits, dogs, cats, pigs, and non-humanprimates, including, but not limited to, monkeys and chimpanzees.

“Antibody,” as used in this disclosure, refers to an immunoglobulin or afragment or a derivative thereof, and encompasses any polypeptidecomprising an antigen-binding site, regardless of whether it is producedin vitro or in vivo. The term includes, but is not limited to,polyclonal, monoclonal, monospecific, polyspecific, non-specific,humanized, single-chain, chimeric, synthetic, recombinant, hybrid,mutated, and grafted antibodies. Unless otherwise modified by the term“intact,” as in “intact antibodies,” for the purposes of thisdisclosure, the term “antibody” also includes antibody fragments such asFab, F(ab′)2, Fv, scFv, Fd, dAb, and other antibody fragments thatretain antigen-binding function, i.e., the ability to bind, for example,CTLA-4 or PD-L1 specifically. Typically, such fragments would comprisean antigen-binding domain.

“Anti-CTLA-4 antibody” refers to an antibody or antigen binding fragmentthereof that specifically binds a CTLA-4 polypeptide. Exemplaryanti-CTLA-4 antibodies are described for example at U.S. Pat. Nos.6,682,736; 7,109,003; 7,123,281; 7,411,057; 7,824,679; 8,143,379;7,807,797; and 8,491,895 (Tremelimumab is 11.2.1, therein), which areherein incorporated by reference. Tremelimumab (U.S. Pat. No. 6,682,736)is an exemplary anti-CTLA-4 antibody. Tremelimumab VL, VH, and CDR aminoacid sequences are provided at SEQ ID NOs: 1-8, herein.

“Anti-OX40 antibody” refers to an antibody or antigen binding fragmentthereof that specifically binds OX40. OX40 antibodies include monoclonaland polyclonal antibodies that are specific for OX40 and antigen-bindingfragments thereof. In certain aspects, anti-OX40 antibodies as describedherein are monoclonal antibodies (or antigen-binding fragments thereof),e.g., murine, humanized, or fully human monoclonal antibodies. In oneparticular embodiment, the OX40 antibody is an OX40 receptor agonist,such as the mouse anti-human OX40 monoclonal antibody (9B12) describedby Weinberg et al., J Immunother 29, 575-585 (2006). In anotherembodiment, an OX40 antibody is MEDI0562 as described in US2016/0137740, incorporated herein by reference. MEDI0562 VH and VL aminoacid sequences are provided at SEQ ID NOs: 25-26, herein. In otherembodiments, the antibody which specifically binds to OX40, or anantigen-binding fragment thereof, binds to the same OX40 epitope as mAb9B12.

“Anti-PD-L1 antibody” refers to an antibody or antigen binding fragmentthereof that specifically binds a PD-L1 polypeptide. Exemplaryanti-PD-L1 antibodies are described for example at US2013/0034559, U.S.Pat. Nos. 8,779,108 and 9,493,565 which are herein incorporated byreference. Durvalumab (MEDI4736) is an exemplary anti-PD-L1 antibody.Durvalumab VL, VH, and CDR amino acid sequences are provided at SEQ IDNOs: 9-16, herein. Other anti-PD-L1 antibodies include BMS-936559(Bristol-Myers Squibb) and MPDL3280A (atezolizumab) (Roche).

“Anti-PD-1 antibody” refers to an antibody or antigen binding fragmentthereof that specifically binds a PD-1 polypeptide. Exemplary anti-PD-1antibodies are described for example at U.S. Pat. Nos. 7,521,051;8,008,449; 8,354,509; 9,073,994; 9,393,301; 9,402,899; and 9,439,962,which are herein incorporated by reference. Exemplary anti-PD-1antibodies include, without limitation, nivolumab, pembrolizumab,pidilizumab, and AMP-514.

“Antigen-binding domain,” “antigen-binding fragment,” and “bindingfragment” refer to a part of an antibody molecule that comprises aminoacids responsible for the specific binding between the antibody and theantigen. In instances, where an antigen is large, the antigen-bindingdomain may only bind to a part of the antigen. A portion of the antigenmolecule that is responsible for specific interactions with theantigen-binding domain is referred to as “epitope” or “antigenicdeterminant.” An antigen-binding domain typically comprises an antibodylight chain variable region (VL) and an antibody heavy chain variableregion (VH), however, it does not necessarily have to comprise both. Forexample, a so-called Fd antibody fragment consists only of a VH domain,but still retains some antigen-binding function of the intact antibody.Binding fragments of an antibody are produced by recombinant DNAtechniques, or by enzymatic or chemical cleavage of intact antibodies.Binding fragments include Fab, Fab′, F(ab′)2, Fv, and single-chainantibodies. An antibody other than a “bispecific” or “bifunctional”antibody is understood to have each of its binding sites identical.Digestion of antibodies with the enzyme, papain, results in twoidentical antigen-binding fragments, known also as “Fab” fragments, anda “Fc” fragment, having no antigen-binding activity but having theability to crystallize. Digestion of antibodies with the enzyme, pepsin,results in the a F(ab′)2 fragment in which the two arms of the antibodymolecule remain linked and comprise two-antigen binding sites. TheF(ab′)2 fragment has the ability to crosslink antigen. “Fv” when usedherein refers to the minimum fragment of an antibody that retains bothantigen-recognition and antigen-binding sites. “Fab” when used hereinrefers to a fragment of an antibody that comprises the constant domainof the light chain and the CH1 domain of the heavy chain.

“mAb” refers to monoclonal antibody. Antibodies of the presentdisclosure comprise without limitation whole native antibodies,bispecific antibodies; chimeric antibodies; Fab, Fab′, single chain Vregion fragments (scFv), fusion polypeptides, and unconventionalantibodies.

“Antisense activity” means any detectable and/or measurable activityattributable to the hybridization of an antisense compound to its targetnucleic acid. In certain embodiments, antisense activity is a decreasein the amount or expression of a target nucleic acid or protein encodedby such target nucleic acid compared to target nucleic acid levels ortarget protein levels in the absence of the antisense compound to thetarget.

“Antisense compound” means a compound comprising an oligonucleotide andoptionally one or more additional features, such as a conjugate group orterminal group. Examples of antisense compounds include single-strandedand double-stranded compounds, such as, oligonucleotides, ribozymes,siRNAs, shRNAs, ssRNAs, and occupancy-based compounds.

“Antisense inhibition” means reduction of target nucleic acid levels inthe presence of an antisense compound complementary to a target nucleicacid compared to target nucleic acid levels in the absence of theantisense compound.

“Antisense mechanisms” are all those mechanisms involving hybridizationof a compound with target nucleic acid, wherein the outcome or effect ofthe hybridization is either target degradation or target occupancy withconcomitant stalling of the cellular machinery involving, for example,transcription or splicing.

“Antisense oligonucleotide” means an oligonucleotide having a nucleobasesequence that is complementary to a target nucleic acid or region orsegment thereof. In certain embodiments, an antisense oligonucleotide isspecifically hybridizable to a target nucleic acid or region or segmentthereof.

“Bicyclic nucleoside” or “BNA” means a nucleoside comprising a bicyclicsugar moiety. “Bicyclic sugar” or “bicyclic sugar moiety” means amodified sugar moiety comprising two rings, wherein the second ring isformed via a bridge connecting two of the atoms in the first ringthereby forming a bicyclic structure. In certain embodiments, the firstring of the bicyclic sugar moiety is a furanosyl moiety. In certainembodiments, the bicyclic sugar moiety does not comprise a furanosylmoiety.

“Branching group” means a group of atoms having at least 3 positionsthat are capable of forming covalent linkages to at least 3 groups. Incertain embodiments, a branching group provides a plurality of reactivesites for connecting tethered ligands to an oligonucleotide via aconjugate linker and/or a cleavable moiety.

“Cell-targeting moiety” means a conjugate group or portion of aconjugate group that is capable of binding to a particular cell type orparticular cell types.

“cEt” or “constrained ethyl” means a bicyclic furanosyl sugar moietycomprising a bridge connecting the 4′-carbon and the 2′-carbon, whereinthe bridge has the formula: 4′-CH(CH₃)—O-2′.

“cEt nucleoside” means a nucleoside comprising a cEt modified sugarmoiety.

“Chemical modification” in a compound describes the substitutions orchanges through chemical reaction, of any of the units in the compoundrelative to the original state of such unit. “Modified nucleoside” meansa nucleoside having, independently, a modified sugar moiety and/ormodified nucleobase. “Modified oligonucleotide” means an oligonucleotidecomprising at least one modified internucleoside linkage, a modifiedsugar, and/or a modified nucleobase.

“Chemically distinct region” refers to a region of a compound that is insome way chemically different than another region of the same compound.For example, a region having 2′-O-methoxyethyl nucleotides is chemicallydistinct from a region having nucleotides without 2′-O-methoxyethylmodifications.

“Chimeric antisense compounds” means antisense compounds that have atleast 2 chemically distinct regions, each position having a plurality ofsubunits.

“Chirally enriched population” means a plurality of molecules ofidentical molecular formula, wherein the number or percentage ofmolecules within the population that contain a particular stereochemicalconfiguration at a particular chiral center is greater than the numberor percentage of molecules expected to contain the same particularstereochemical configuration at the same particular chiral center withinthe population if the particular chiral center were stereorandom.Chirally enriched populations of molecules having multiple chiralcenters within each molecule may contain one or more stereorandom chiralcenters. In certain embodiments, the molecules are modifiedoligonucleotides. In certain embodiments, the molecules are compoundscomprising modified oligonucleotides.

“Cleavable bond” means any chemical bond capable of being split. Incertain embodiments, a cleavable bond is selected from among: an amide,a polyamide, an ester, an ether, one or both esters of a phosphodiester,a phosphate ester, a carbamate, a di-sulfide, or a peptide.

“Cleavable moiety” means a bond or group of atoms that is cleaved underphysiological conditions, for example, inside a cell, an animal, or ahuman.

“Complementary” in reference to an oligonucleotide means the nucleobasesequence of such oligonucleotide or one or more regions thereof matchesthe nucleobase sequence of another oligonucleotide or nucleic acid orone or more regions thereof when the two nucleobase sequences arealigned in opposing directions. Nucleobase matches or complementarynucleobases, as described herein, are limited to the following pairs:adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine (C)and guanine (G), and 5-methyl cytosine (^(m)C) and guanine (G) unlessotherwise specified. Complementary oligonucleotides and/or nucleic acidsneed not have nucleobase complementarity at each nucleoside and mayinclude one or more nucleobase mismatches. By contrast, “fullycomplementary” or “100% complementary” in reference to oligonucleotidesmeans that such oligonucleotides have nucleobase matches at eachnucleoside without any nucleobase mismatches.

“Conjugate group” means a group of atoms that is attached to anoligonucleotide. Conjugate groups include a conjugate moiety and aconjugate linker that attaches the conjugate moiety to theoligonucleotide.

“Conjugate linker” means a group of atoms comprising at least one bondthat connects a conjugate moiety to an oligonucleotide.

“Conjugate moiety” means a group of atoms that is attached to anoligonucleotide via a conjugate linker.

“Contiguous” in the context of an oligonucleotide refers to nucleosides,nucleobases, sugar moieties, or internucleoside linkages that areimmediately adjacent to each other. For example, “contiguousnucleobases” means nucleobases that are immediately adjacent to eachother in a sequence.

“Designing” or “Designed to” refer to the process of designing acompound that specifically hybridizes with a selected nucleic acidmolecule.

“Diluent” means an ingredient in a composition that lackspharmacological activity, but is pharmaceutically necessary ordesirable. For example, the diluent in an injected composition can be aliquid, e.g. saline solution.

“Differently modified” means chemical modifications or chemicalsubstituents that are different from one another, including absence ofmodifications. Thus, for example, a MOE nucleoside and an unmodified DNAnucleoside are “differently modified,” even though the DNA nucleoside isunmodified. Likewise, DNA and RNA are “differently modified,” eventhough both are naturally-occurring unmodified nucleosides. Nucleosidesthat are the same but for comprising different nucleobases are notdifferently modified. For example, a nucleoside comprising a 2′-OMemodified sugar and an unmodified adenine nucleobase and a nucleosidecomprising a 2′-OMe modified sugar and an unmodified thymine nucleobaseare not differently modified.

“Dose” means a specified quantity of a compound or pharmaceutical agentprovided in a single administration, or in a specified time period. Incertain embodiments, a dose may be administered in two or more boluses,tablets, or injections. For example, in certain embodiments, wheresubcutaneous administration is desired, the desired dose may require avolume not easily accommodated by a single injection. In suchembodiments, two or more injections may be used to achieve the desireddose. In certain embodiments, a dose may be administered in two or moreinjections to minimize injection site reaction in an individual. Inother embodiments, the compound or pharmaceutical agent is administeredby infusion over an extended period of time or continuously. Doses maybe stated as the amount of pharmaceutical agent per hour, day, week ormonth.

“Dosing regimen” is a combination of doses designed to achieve one ormore desired effects.

“Double-stranded antisense compound” means an antisense compoundcomprising two oligomeric compounds that are complementary to each otherand form a duplex, and wherein one of the two said oligomeric compoundscomprises an oligonucleotide.

“Effective amount” means the amount of compound sufficient to effectuatea desired physiological outcome in an individual in need of thecompound. The effective amount may vary among individuals depending onthe health and physical condition of the individual to be treated, thetaxonomic group of the individuals to be treated, the formulation of thecomposition, assessment of the individual's medical condition, and otherrelevant factors.

“Efficacy” means the ability to produce a desired effect.

“Expression” includes all the functions by which a gene's codedinformation is converted into structures present and operating in acell. Such structures include, but are not limited to, the products oftranscription and translation.

“Gapmer” means an oligonucleotide comprising an internal region having aplurality of nucleosides that support RNase H cleavage positionedbetween external regions having one or more nucleosides, wherein thenucleosides comprising the internal region are chemically distinct fromthe nucleoside or nucleosides comprising the external regions. Theinternal region may be referred to as the “gap” and the external regionsmay be referred to as the “wings.”

“Hybridization” means the annealing of oligonucleotides and/or nucleicacids. While not limited to a particular mechanism, the most commonmechanism of hybridization involves hydrogen bonding, which may beWatson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, betweencomplementary nucleobases. In certain embodiments, complementary nucleicacid molecules include, but are not limited to, an antisense compoundand a nucleic acid target. In certain embodiments, complementary nucleicacid molecules include, but are not limited to, an oligonucleotide and anucleic acid target.

“Immediately adjacent” means there are no intervening elements betweenthe immediately adjacent elements of the same kind (e.g. no interveningnucleobases between the immediately adjacent nucleobases).

“Immune checkpoint inhibitor” means an agent that inhibits theexpression or activity of a protein that inhibits an immune response. Inone embodiment, an immune checkpoint inhibitor is an agent that inhibitsthe CTLA-4 or PD-1 pathways. Particular checkpoint inhibitors includeantibodies that inhibit PD-1, PD-L1 or CTLA-4.

“Immunomodulatory agent” means an agent that enhances an immune response(e.g., anti-tumor immune response). Exemplary immunomodulatory agents ofthe present disclosure include antibodies, such as an anti-CTLA-4antibody, an anti-PD-L1 antibody, an anti-PD-1 antibody and antigenicfragments of any of these, and OX40 agonists, including proteins, suchas OX40 ligand fusion protein, OX40 antibody, or fragments thereof. Inone embodiment, the immunomodulatory agent is an immune checkpointinhibitor.

“Individual” means a human or non-human animal selected for treatment ortherapy.

“Inhibiting the expression or activity” refers to a reduction orblockade of the expression or activity relative to the expression ofactivity in an untreated or control sample and does not necessarilyindicate a total elimination of expression or activity.

“Internucleoside linkage” means a group or bond that forms a covalentlinkage between adjacent nucleosides in an oligonucleotide. “Modifiedinternucleoside linkage” means any internucleoside linkage other than anaturally occurring, phosphate internucleoside linkage. Non-phosphatelinkages are referred to herein as modified internucleoside linkages.

“Lengthened oligonucleotides” are those that have one or more additionalnucleosides relative to an oligonucleotide disclosed herein, e.g. aparent oligonucleotide.

“Linked nucleosides” means adjacent nucleosides linked together by aninternucleoside linkage.

“Linker-nucleoside” means a nucleoside that links an oligonucleotide toa conjugate moiety. Linker-nucleosides are located within the conjugatelinker of a compound. Linker-nucleosides are not considered part of theoligonucleotide portion of a compound even if they are contiguous withthe oligonucleotide.

“Mismatch” or “non-complementary” means a nucleobase of a firstoligonucleotide that is not complementary to the correspondingnucleobase of a second oligonucleotide or target nucleic acid when thefirst and second oligonucleotides are aligned. For example, nucleobasesincluding but not limited to a universal nucleobase, inosine, andhypoxanthine, are capable of hybridizing with at least one nucleobasebut are still mismatched or non-complementary with respect to nucleobaseto which it hybridized. As another example, a nucleobase of a firstoligonucleotide that is not capable of hybridizing to the correspondingnucleobase of a second oligonucleotide or target nucleic acid when thefirst and second oligonucleotides are aligned is a mismatch ornon-complementary nucleobase.

“Modulating” refers to changing or adjusting a feature in a cell,tissue, organ or organism. For example, modulating MALAT1 RNA can meanto increase or decrease the level of MALAT1 RNA and/or MALAT1 protein ina cell, tissue, organ or organism. A “modulator” effects the change inthe cell, tissue, organ or organism. For example, a MALAT1 compound canbe a modulator that decreases the amount of MALAT1 RNA and/or MALAT1protein in a cell, tissue, organ or organism.

“MOE” means methoxyethyl.

“Monomer” refers to a single unit of an oligomer. Monomers include, butare not limited to, nucleosides and nucleotides.

“Motif” means the pattern of unmodified and/or modified sugar moieties,nucleobases, and/or internucleoside linkages, in an oligonucleotide.

“Natural” or “naturally occurring” means found in nature.

“Non-bicyclic modified sugar” or “non-bicyclic modified sugar moiety”means a modified sugar moiety that comprises a modification, such as asubstituent, that does not form a bridge between two atoms of the sugarto form a second ring.

“Nucleic acid” refers to molecules composed of monomeric nucleotides. Anucleic acid includes, but is not limited to, ribonucleic acids (RNA),deoxyribonucleic acids (DNA), single-stranded nucleic acids, anddouble-stranded nucleic acids.

“Nucleobase” means a heterocyclic moiety capable of pairing with a baseof another nucleic acid. As used herein a “naturally occurringnucleobase” is adenine (A), thymine (T), cytosine (C), uracil (U), andguanine (G). A “modified nucleobase” is a naturally occurring nucleobasethat is chemically modified. A “universal base” or “universalnucleobase” is a nucleobase other than a naturally occurring nucleobaseand modified nucleobase, and is capable of pairing with any nucleobase.

“Nucleobase sequence” means the order of contiguous nucleobases in anucleic acid or oligonucleotide independent of any sugar orinternucleoside linkage.

“Nucleoside” means a compound comprising a nucleobase and a sugarmoiety. The nucleobase and sugar moiety are each, independently,unmodified or modified. “Modified nucleoside” means a nucleosidecomprising a modified nucleobase and/or a modified sugar moiety.Modified nucleosides include abasic nucleosides, which lack anucleobase.

“Oligomeric compound” means a compound comprising a singleoligonucleotide and optionally one or more additional features, such asa conjugate group or terminal group.

“Oligonucleotide” means a polymer of linked nucleosides each of whichcan be modified or unmodified, independent one from another. Unlessotherwise indicated, oligonucleotides consist of 8-80 linkednucleosides. “Modified oligonucleotide” means an oligonucleotide,wherein at least one sugar, nucleobase, or internucleoside linkage ismodified. “Unmodified oligonucleotide” means an oligonucleotide thatdoes not comprise any sugar, nucleobase, or internucleosidemodification.

“Parent oligonucleotide” means an oligonucleotide whose sequence is usedas the basis of design for more oligonucleotides of similar sequence butwith different lengths, motifs, and/or chemistries. The newly designedoligonucleotides may have the same or overlapping sequence as the parentoligonucleotide.

“Parenteral administration” means administration through injection orinfusion. Parenteral administration includes subcutaneousadministration, intravenous administration, intramuscularadministration, intraarterial administration, intraperitonealadministration, or intracranial administration, e.g. intrathecal orintracerebroventricular administration.

“Pharmaceutically acceptable carrier or diluent” means any substancesuitable for use in administering to an individual. For example, apharmaceutically acceptable carrier can be a sterile aqueous solution,such as PBS or water-for-injection.

“Pharmaceutically acceptable salts” means physiologically andpharmaceutically acceptable salts of compounds, such as oligomericcompounds or oligonucleotides, i.e., salts that retain the desiredbiological activity of the parent compound and do not impart undesiredtoxicological effects thereto.

“Pharmaceutical agent” means a compound that provides a therapeuticbenefit when administered to an individual.

“Pharmaceutical composition” means a mixture of substances suitable foradministering to an individual. For example, a pharmaceuticalcomposition may comprise one or more compounds or salt thereof and asterile aqueous solution.

“Phosphorothioate linkage” means a modified phosphate linkage in whichone of the non-bridging oxygen atoms is replaced with a sulfur atom. Aphosphorothioate internucleoside linkage is a modified internucleosidelinkage.

“Phosphorus moiety” means a group of atoms comprising a phosphorus atom.In certain embodiments, a phosphorus moiety comprises a mono-, di-, ortri-phosphate, or phosphorothioate.

“Portion” means a defined number of contiguous (i.e., linked)nucleobases of a nucleic acid. In certain embodiments, a portion is adefined number of contiguous nucleobases of a target nucleic acid. Incertain embodiments, a portion is a defined number of contiguousnucleobases of an oligomeric compound.

“Prevent” refers to delaying or forestalling the onset, development orprogression of a disease, disorder, or condition for a period of timefrom minutes to indefinitely.

“Prodrug” means a compound in a form outside the body which, whenadministered to an individual, is metabolized to another form within thebody or cells thereof. In certain embodiments, the metabolized form isthe active, or more active, form of the compound (e.g., drug). Typicallyconversion of a prodrug within the body is facilitated by the action ofan enzyme(s) (e.g., endogenous or viral enzyme) or chemical(s) presentin cells or tissues, and/or by physiologic conditions.

“Reduce” means to bring down to a smaller extent, size, amount, ornumber.

“RefSeq No.” is a unique combination of letters and numbers assigned toa sequence to indicate the sequence is for a particular targettranscript (e.g., target gene). Such sequence and information about thetarget gene (collectively, the gene record) can be found in a geneticsequence database. Genetic sequence databases include the NCBI ReferenceSequence database, GenBank, the European Nucleotide Archive, and the DNAData Bank of Japan (the latter three forming the InternationalNucleotide Sequence Database Collaboration or INSDC).

“Region” is defined as a portion of the target nucleic acid having atleast one identifiable structure, function, or characteristic.

“RNAi compound” means an antisense compound that acts, at least in part,through RISC or Ago2, but not through RNase H, to modulate a targetnucleic acid and/or protein encoded by a target nucleic acid. RNAicompounds include, but are not limited to double-stranded siRNA,single-stranded RNA (ssRNA), and microRNA, including microRNA mimics.

“Segments” are defined as smaller or sub-portions of regions within anucleic acid.

“Side effects” means physiological disease and/or conditionsattributable to a treatment other than the desired effects. In certainembodiments, side effects include injection site reactions, liverfunction test abnormalities, renal function abnormalities, livertoxicity, renal toxicity, central nervous system abnormalities,myopathies, and malaise. For example, increased aminotransferase levelsin serum may indicate liver toxicity or liver function abnormality. Forexample, increased bilirubin may indicate liver toxicity or liverfunction abnormality.

“Single-stranded” in reference to a compound means the compound has onlyone oligonucleotide. “Self-complementary” means an oligonucleotide thatat least partially hybridizes to itself. A compound consisting of oneoligonucleotide, wherein the oligonucleotide of the compound isself-complementary, is a single-stranded compound. A single-strandedcompound may be capable of binding to a complementary compound to form aduplex.

“Sites” are defined as unique nucleobase positions within a targetnucleic acid.

“Specifically hybridizable” refers to an oligonucleotide having asufficient degree of complementarity between the oligonucleotide and atarget nucleic acid to induce a desired effect, while exhibiting minimalor no effects on non-target nucleic acids. In certain embodiments,specific hybridization occurs under physiological conditions.

“Specifically inhibit” with reference to a target nucleic acid means toreduce or block expression of the target nucleic acid while exhibitingfewer, minimal, or no effects on non-target nucleic acids. Reductiondoes not necessarily indicate a total elimination of the target nucleicacid's expression.

“Standard cell assay” means assay(s) described in the Examples andreasonable variations thereof

“Standard in vivo experiment” means the procedure(s) described in theExample(s) and reasonable variations thereof.

“Stereorandom chiral center” in the context of a population of moleculesof identical molecular formula means a chiral center having a randomstereochemical configuration. For example, in a population of moleculescomprising a stereorandom chiral center, the number of molecules havingthe (S) configuration of the stereorandom chiral center may be but isnot necessarily the same as the number of molecules having the (R)configuration of the stereorandom chiral center. The stereochemicalconfiguration of a chiral center is considered random when it is theresult of a synthetic method that is not designed to control thestereochemical configuration. In certain embodiments, a stereorandomchiral center is a stereorandom phosphorothioate internucleosidelinkage.

“Sugar moiety” means an unmodified sugar moiety or a modified sugarmoiety. “Unmodified sugar moiety” or “unmodified sugar” means a 2′-OH(H)furanosyl moiety, as found in RNA (an “unmodified RNA sugar moiety”), ora 2′-H(H) moiety, as found in DNA (an “unmodified DNA sugar moiety”).Unmodified sugar moieties have one hydrogen at each of the 1′, 3′, and4′ positions, an oxygen at the 3′ position, and two hydrogens at the 5′position. “Modified sugar moiety” or “modified sugar” means a modifiedfuranosyl sugar moiety or a sugar surrogate. “Modified furanosyl sugarmoiety” means a furanosyl sugar comprising a non-hydrogen substituent inplace of at least one hydrogen of an unmodified sugar moiety. In certainembodiments, a modified furanosyl sugar moiety is a 2′-substituted sugarmoiety. Such modified furanosyl sugar moieties include bicyclic sugarsand non-bicyclic sugars.

“Sugar surrogate” means a modified sugar moiety having other than afuranosyl moiety that can link a nucleobase to another group, such as aninternucleoside linkage, conjugate group, or terminal group in anoligonucleotide. Modified nucleosides comprising sugar surrogates can beincorporated into one or more positions within an oligonucleotide andsuch oligonucleotides are capable of hybridizing to complementarycompounds or nucleic acids.

“Synergy” or “synergize” refers to an effect of a combination that isgreater than additive of the effects of each component alone at the samedoses.

“MALAT1” means any nucleic acid or protein of MALAT1. “MALAT1 nucleicacid” means any nucleic acid encoding MALAT1. For example, in certainembodiments, a MALAT1 nucleic acid includes a DNA sequence encodingMALAT1, an RNA sequence transcribed from DNA encoding MALAT1 (includinggenomic DNA comprising introns and exons), and an mRNA sequence encodingMALAT1. “MALAT1 mRNA” means an mRNA encoding a MALAT1 protein. Thetarget may be referred to in either upper or lower case.

“MALAT1 specific inhibitor” refers to any agent capable of specificallyinhibiting MALAT1 RNA and/or MALAT1 protein expression or activity atthe molecular level. For example, MALAT1 specific inhibitors includenucleic acids (including antisense compounds), peptides, antibodies,small molecules, and other agents capable of inhibiting the expressionof MALAT1 RNA and/or MALAT1 protein.

“Target gene” refers to a gene encoding a target.

“Targeting” means the specific hybridization of a compound to a targetnucleic acid in order to induce a desired effect.

“Target nucleic acid,” “target RNA,” “target RNA transcript” and“nucleic acid target” all mean a nucleic acid capable of being targetedby compounds described herein.

“Target region” means a portion of a target nucleic acid to which one ormore compounds is targeted.

“Target segment” means the sequence of nucleotides of a target nucleicacid to which a compound is targeted. “5′ target site” refers to the5′-most nucleotide of a target segment. “3′ target site” refers to the3′-most nucleotide of a target segment.

“Terminal group” means a chemical group or group of atoms that iscovalently linked to a terminus of an oligonucleotide.

“Therapeutically effective amount” means an amount of a compound,pharmaceutical agent, or composition that provides a therapeutic benefitto an individual.

“Treat” refers to administering a compound or pharmaceutical compositionto an animal in order to effect an alteration or improvement of adisease, disorder, or condition in the animal.

CERTAIN EMBODIMENTS

Certain embodiments provide methods, compounds and compositions forinhibiting MALAT1 expression.

Certain embodiments provide compounds targeted to a MALAT1 nucleic acid.In certain embodiments, the MALAT1 nucleic acid has the sequence setforth in RefSeq or GENBANK Accession No. XR_001309.1 (SEQ ID NO: 1)(which is incorporated by reference in its entirety), or GENBANKAccession No. EF177381.1 (SEQ ID NO: 2824) (which is incorporated byreference in its entirety). In certain embodiments, the compound is anantisense compound or oligomeric compound. In certain embodiments, thecompound is single-stranded. In certain embodiments, the compound isdouble-stranded.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 8 to 80 linked nucleosides and having anucleobase sequence comprising at least 8 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 2-10 or 36-2813. In certainembodiments, the compound is an antisense compound or oligomericcompound. In certain embodiments, the compound is single-stranded. Incertain embodiments, the compound is double-stranded. In certainembodiments, the modified oligonucleotide consists of 10 to 30 linkednucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 8 to 80 linked nucleosides and having anucleobase sequence comprising at least 8 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 2-10. In certain embodiments,the compound is an antisense compound or oligomeric compound. In certainembodiments, the compound is single-stranded. In certain embodiments,the compound is double-stranded. In certain embodiments, the modifiedoligonucleotide consists of 10 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 9 to 80 linked nucleosides and having anucleobase sequence comprising at least 9 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 2-10 or 36-2813. In certainembodiments, the compound is an antisense compound or oligomericcompound. In certain embodiments, the compound is single-stranded. Incertain embodiments, the compound is double-stranded. In certainembodiments, the modified oligonucleotide consists of 10 to 30 linkednucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 9 to 80 linked nucleosides and having anucleobase sequence comprising at least 9 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 2-10. In certain embodiments,the compound is an antisense compound or oligomeric compound. In certainembodiments, the compound is single-stranded. In certain embodiments,the compound is double-stranded. In certain embodiments, the modifiedoligonucleotide consists of 10 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 10 to 80 linked nucleosides and having anucleobase sequence comprising at least 10 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 2-10 or 36-2813. In certainembodiments, the compound is an antisense compound or oligomericcompound. In certain embodiments, the compound is single-stranded. Incertain embodiments, the compound is double-stranded. In certainembodiments, the modified oligonucleotide consists of 10 to 30 linkednucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 10 to 80 linked nucleosides and having anucleobase sequence comprising at least 10 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 2-10. In certain embodiments,the compound is an antisense compound or oligomeric compound. In certainembodiments, the compound is single-stranded. In certain embodiments,the compound is double-stranded. In certain embodiments, the modifiedoligonucleotide consists of 10 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 11 to 80 linked nucleosides and having anucleobase sequence comprising at least 11 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 2-10 or 36-2813. In certainembodiments, the compound is an antisense compound or oligomericcompound. In certain embodiments, the compound is single-stranded. Incertain embodiments, the compound is double-stranded. In certainembodiments, the modified oligonucleotide consists of 11 to 30 linkednucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 11 to 80 linked nucleosides and having anucleobase sequence comprising at least 11 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 2-10. In certain embodiments,the compound is an antisense compound or oligomeric compound. In certainembodiments, the compound is single-stranded. In certain embodiments,the compound is double-stranded. In certain embodiments, the modifiedoligonucleotide consists of 11 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 12 to 80 linked nucleosides and having anucleobase sequence comprising at least 12 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 2-10 or 36-2813. In certainembodiments, the compound is an antisense compound or oligomericcompound. In certain embodiments, the compound is single-stranded. Incertain embodiments, the compound is double-stranded. In certainembodiments, the modified oligonucleotide consists of 12 to 30 linkednucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 12 to 80 linked nucleosides and having anucleobase sequence comprising at least 12 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 2-10. In certain embodiments,the compound is an antisense compound or oligomeric compound. In certainembodiments, the compound is single-stranded. In certain embodiments,the compound is double-stranded. In certain embodiments, the modifiedoligonucleotide consists of 12 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 16 to 80 linked nucleosides and having anucleobase sequence comprising the nucleobase sequence of any one of SEQID NOs: 2-10 or 36-2813. In certain embodiments, the compound is anantisense compound or oligomeric compound. In certain embodiments, thecompound is single-stranded. In certain embodiments, the compound isdouble-stranded. In certain embodiments, the modified oligonucleotideconsists of 16 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 16 to 80 linked nucleosides and having anucleobase sequence comprising the nucleobase sequence of any one of SEQID NOs: 2-10. In certain embodiments, the compound is an antisensecompound or oligomeric compound. In certain embodiments, the compound issingle-stranded. In certain embodiments, the compound isdouble-stranded. In certain embodiments, the modified oligonucleotideconsists of 16 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide having a nucleobase sequence consisting of thenucleobase sequence of any one of SEQ ID NOs: 2-10 or 36-2813. Incertain embodiments, the compound is an antisense compound or oligomericcompound. In certain embodiments, the compound is single-stranded. Incertain embodiments, the compound is double-stranded.

Certain embodiments provide a compound comprising a modifiedoligonucleotide having a nucleobase sequence consisting of thenucleobase sequence of any one of SEQ ID NOs: 2-10. In certainembodiments, the compound is an antisense compound or oligomericcompound. In certain embodiments, the compound is single-stranded. Incertain embodiments, the compound is double-stranded.

In certain embodiments, a compound comprises a modified oligonucleotideconsisting of 8 to 80 linked nucleosides wherein the nucleobase sequenceof the modified oligonucleotide comprises an at least 8, 9, 10, 11, 12,13, 14, 15, or 16 contiguous nucleobase portion complementary to anequal length portion within nucleotides 1535-1550, 2034-2049, 2341-2356,4821-4836, 4840-4855, 4931-4946, 5049-5064, 5494-5509, or 5495-5510 ofSEQ ID NO: 1. In certain embodiments, the modified oligonucleotideconsists of 10 to 30 linked nucleosides. In certain embodiments, themodified oligonucleotide consists of 16 to 30 linked nucleosides.

In certain embodiments, a compound comprises a modified oligonucleotideconsisting of 8 to 80 linked nucleosides wherein the nucleobase sequenceof the modified oligonucleotide is complementary within nucleotides1535-1550, 2034-2049, 2341-2356, 4821-4836, 4840-4855, 4931-4946,5049-5064, 5494-5509, or 5495-5510 of SEQ ID NO: 1. In certainembodiments, the modified oligonucleotide consists of 10 to 30 linkednucleosides. In certain embodiments, the modified oligonucleotideconsists of 16 to 30 linked nucleosides.

In certain embodiments, a compound comprises a modified oligonucleotideconsisting of 8 to 80 linked nucleosides and having a nucleobasesequence comprising at least an 8, 9, 10, 11, 12, 13, 14, 15, or 16contiguous nucleobase portion of the nucleobase sequence of any one ofSEQ ID NOs: 2-10 or 36-2813. In certain embodiments, the modifiedoligonucleotide consists of 10 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 to 30 linkednucleosides.

In certain embodiments, a compound comprises a modified oligonucleotideconsisting of 8 to 80 linked nucleosides and having a nucleobasesequence comprising at least an 8, 9, 10, 11, 12, 13, 14, 15, or 16contiguous nucleobase portion of the nucleobase sequence of any one ofSEQ ID NOs: 2-10. In certain embodiments, the modified oligonucleotideconsists of 10 to 30 linked nucleosides. In certain embodiments, themodified oligonucleotide consists of 16 to 30 linked nucleosides.

In certain embodiments, a compound comprises a modified oligonucleotideconsisting of 16 to 80 linked nucleosides and having a nucleobasesequence comprising the nucleobase sequence of any one of SEQ ID NOs:2-10 or 36-2813. In certain embodiments, the modified oligonucleotideconsists of 16 to 30 linked nucleosides.

In certain embodiments, a compound comprises a modified oligonucleotideconsisting of 16 to 80 linked nucleosides and having a nucleobasesequence comprising the nucleobase sequence of any one of SEQ ID NOs:2-10. In certain embodiments, the modified oligonucleotide consists of16 to 30 linked nucleosides.

In certain embodiments, a compound comprises a modified oligonucleotideconsisting of 16 linked nucleosides and having a nucleobase sequenceconsisting of the nucleobase sequence of any one of SEQ ID NOs: 2-10 or36-2813.

In certain embodiments, a compound comprises a modified oligonucleotideconsisting of 16 linked nucleosides and having a nucleobase sequenceconsisting of the nucleobase sequence of any one of SEQ ID NOs: 2-10.

In certain embodiments, at least one internucleoside linkage of any ofthe foregoing modified oligonucleotides is a modified internucleosidelinkage, at least one sugar of any of the foregoing modifiedoligonucleotides is a modified sugar, and/or at least one nucleobase ofany of the foregoing modified oligonucleotides is a modified nucleobase.

In certain embodiments, at least one nucleoside of any of the foregoingmodified oligonucleotides comprises a modified sugar. In certainembodiments, the modified sugar comprises a 2′-O-methoxyethyl group. Incertain embodiments, the modified sugar is a bicyclic sugar, such as a4′-CH(CH₃)—O-2′ group, a 4′-CH₂—O-2′ group, or a 4′-(CH₂)₂—O-2′ group.

In certain embodiments, at least one internucleoside linkage of themodified oligonucleotide is a modified internucleoside linkage, such asa phosphorothioate internucleoside linkage.

In certain embodiments, at least one nucleobase of any of the foregoingmodified oligonucleotides is a modified nucleobase, such as5-methylcytosine.

In certain embodiments, any of the foregoing modified oligonucleotideshas:

-   -   a gap segment consisting of linked 2′-deoxynucleosides;    -   a 5′ wing segment consisting of linked nucleosides; and    -   a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment and wherein each nucleoside of each wing segmentcomprises a modified sugar. In certain embodiments, the modifiedoligonucleotide consists of 16 to 80 linked nucleosides and has anucleobase sequence comprising the nucleobase sequence recited in anyone of SEQ ID NOs: 2-10 or 36-2813. In certain embodiments, the modifiedoligonucleotide consists of 16 to 80 linked nucleosides and has anucleobase sequence comprising the nucleobase sequence recited in anyone of SEQ ID NOs: 2-10. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides and has anucleobase sequence comprising the nucleobase sequence recited in anyone of SEQ ID NOs: 2-10 or 36-2813. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides and has anucleobase sequence comprising the nucleobase sequence recited in anyone of SEQ ID NOs: 2-10. In certain embodiments, the modifiedoligonucleotide consists of 16 linked nucleosides and has a nucleobasesequence consisting of the nucleobase sequence recited in any one of SEQID NOs: 2-10 or 36-2813. In certain embodiments, the modifiedoligonucleotide consists of 16 linked nucleosides and has a nucleobasesequence consisting of the nucleobase sequence recited in any one of SEQID NOs: 2-10.

In certain embodiments, a compound comprises or consists of a modifiedoligonucleotide consisting of 16 to 80 linked nucleobases and having anucleobase sequence comprising the nucleobase sequence recited in anyone of SEQ ID NOs: 2-10 or 36-2813, wherein the modified oligonucleotidehas:

-   -   a gap segment consisting of linked 2′-deoxynucleosides;    -   a 5′ wing segment consisting of linked nucleosides; and    -   a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment and wherein each nucleoside of each wing segmentcomprises a modified sugar. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 linkednucleosides.

In certain embodiments, a compound comprises or consists of a modifiedoligonucleotide consisting of 16 to 80 linked nucleobases and having anucleobase sequence comprising the nucleobase sequence recited in anyone of SEQ ID NOs: 2-10, wherein the modified oligonucleotide has:

-   -   a gap segment consisting of linked 2′-deoxynucleosides;    -   a 5′ wing segment consisting of linked nucleosides; and    -   a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment and wherein each nucleoside of each wing segmentcomprises a modified sugar. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 linkednucleosides.

In certain embodiments, a compound comprises or consists of a modifiedoligonucleotide consisting of 16 to 80 linked nucleobases and having anucleobase sequence comprising the nucleobase sequence recited in anyone of SEQ ID NOs: 36-2646 or 2664-2813, wherein the modifiedoligonucleotide has:

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment; wherein each nucleoside of each wing segmentcomprises a cEt nucleoside; wherein each internucleoside linkage is aphosphorothioate linkage; and wherein each cytosine is 5-methylcytosine.In certain embodiments, the modified oligonucleotide consists of 16 to30 linked nucleosides. In certain embodiments, the modifiedoligonucleotide consists of 16 linked nucleosides.

In certain embodiments, a compound comprises or consists of a modifiedoligonucleotide consisting of 16 to 80 linked nucleobases and having anucleobase sequence comprising the nucleobase sequence recited in anyone of SEQ ID NOs: 2-7, wherein the modified oligonucleotide has:

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment; wherein each nucleoside of each wing segmentcomprises a cEt nucleoside; wherein each internucleoside linkage is aphosphorothioate linkage; and wherein each cytosine is 5-methylcytosine.In certain embodiments, the modified oligonucleotide consists of 16 to30 linked nucleosides. In certain embodiments, the modifiedoligonucleotide consists of 16 linked nucleosides.

In certain embodiments, a compound comprises or consists of a modifiedoligonucleotide having a nucleobase sequence comprising the nucleobasesequence recited in any of SEQ ID NOs: 8-10; wherein the modifiedoligonucleotide comprises the sugar motif kkk-d-y-d(8)-kkk, wherein “k”indicates a cEt modified sugar moiety, “d” indicates an unmodified2′-deoxyribosyl sugar moiety, and “y” indicates a 2′-O-methyl modifiedsugar moiety; wherein each internucleoside linkage is a phosphorothioatelinkage; and wherein each cytosine is 5-methylcytosine. In certainembodiments, the modified oligonucleotide consisting of 16 to 30 linkednucleosides. In certain embodiments, the modified oligonucleotideconsists of 16 linked nucleosides.

In certain embodiments, a compound comprises or consists of ION 1304884having the nucleobase sequence and chemical motif:GksGksAksTdsUysAdsAdsTdsGdsTdsAdsGdsTdsGksTksAk (SEQ ID NO: 8), wherein“d” represents a 2′-deoxyribose sugar, “k” represents a cEt modifiedsugar, “y” represents a 2′-O-methyl modified sugar, “s” represents aphosphorothioate internucleoside linkage, and “mC” refers to5-methylcytosine. In certain embodiments, the modified oligonucleotideconsists of 16 to 30 linked nucleosides. In certain embodiments, themodified oligonucleotide consists of 16 linked nucleosides.

In certain embodiments, a compound comprises or consists of ION 1304890having the nucleobase sequence and chemical motif:GksGksTksTdsAysTdsAdsGdsmCdsTdsTdsGdsAdsmCksAksAk (SEQ ID NO: 9),wherein “d” represents a 2′-deoxyribose sugar, “k” represents a cEtmodified sugar, “y” represents a 2′-O-methyl modified sugar, “s”represents a phosphorothioate internucleoside linkage, and “mC” refersto a 5-methylcytosine. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 linkednucleosides.

In certain embodiments, a compound comprises or consists of ION 1304906having the nucleobase sequence and chemical motif:GksmCksAksGdsAysTdsAdsAdsTdsGdsTdsTdsmCdsTksmCksAk (SEQ ID NO: 10),wherein “d” represents a 2′-deoxyribose sugar, “k” represents a cEtmodified sugar, “y” represents a 2′-O-methyl modified sugar, “s”represents a phosphorothioate internucleoside linkage, and “mC” refersto 5-methylcytosine. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 linkednucleosides.

Certain embodiments provide a modified oligonucleotide according to thefollowing chemical structure:

or a salt thereof. In certain embodiments, the modified oligonucleotideis the sodium salt or potassium salt.

Certain embodiments provide a modified oligonucleotide according to thefollowing chemical structure:

Under certain conditions, certain compounds disclosed herein act asacids. Although such compounds may be drawn or described in protonated(free acid) form, or ionized and in association with a cation (salt)form, aqueous solutions of such compounds exist in equilibrium amongsuch forms. For example, a phosphate linkage of an oligonucleotide inaqueous solution exists in equilibrium among free acid, anion and saltforms. Unless otherwise indicated, compounds described herein areintended to include all such forms. Moreover, certain oligonucleotideshave several such linkages, each of which is in equilibrium. Thus,oligonucleotides in solution exist in an ensemble of forms at multiplepositions all at equilibrium. Unless otherwise indicated, anoligonucleotide described herein and the term “oligonucleotide” areintended to include all such forms. Drawn structures necessarily depicta single form. Nevertheless, unless otherwise indicated, such drawingsare likewise intended to include corresponding forms. Herein, astructure depicting the free acid of a compound followed by the term “ora salt thereof” expressly includes all such forms that may be fully orpartially protonated/de-protonated/in association with a cation. Incertain instances, one or more specific cation is identified.

In any of the foregoing embodiments, the compound or oligonucleotide canbe at least 85%, at least 90%, at least 95%, at least 98%, at least 99%,or 100% complementary to a nucleic acid encoding MALAT1.

In any of the foregoing embodiments, the compound can besingle-stranded. In certain embodiments, the compound comprisesdeoxyribonucleotides. In certain embodiments, the compound isdouble-stranded. In certain embodiments, the compound is double-strandedand comprises ribonucleotides. In any of the foregoing embodiments, thecompound can be an antisense compound or oligomeric compound.

In any of the foregoing embodiments, the compound can consisting of 8 to80, 10 to 30, 12 to 50, 13 to 30, 13 to 50, 14 to 30, 14 to 50, 15 to30, 15 to 50, 16 to 30, 16 to 50, 17 to 30, 17 to 50, 18 to 22, 18 to24, 18 to 30, 18 to 50, 19 to 22, 19 to 30, 19 to 50, or 20 to 30 linkednucleosides. In certain embodiments, the compound comprises or consistsof an oligonucleotide.

In certain embodiments, compounds or compositions provided hereincomprise a salt of the modified oligonucleotide. In certain embodiments,the salt is a sodium salt. In certain embodiments, the salt is apotassium salt.

In certain embodiments, the compounds or compositions as describedherein are highly tolerable as demonstrated by having at least one of anincrease an alanine transaminase (ALT) or aspartate transaminase (AST)value of no more than 4 fold, 3 fold, or 2 fold over saline treatedanimals or an increase in liver, spleen, or kidney weight of no morethan 30%, 20%, 15%, 12%, 10%, 5%, or 2% compared to control treatedanimals. In certain embodiments, the compounds or compositions asdescribed herein are highly tolerable as demonstrated by having noincrease of ALT or AST over control treated animals. In certainembodiments, the compounds or compositions as described herein arehighly tolerable as demonstrated by having no increase in liver, spleen,or kidney weight over control animals.

Certain embodiments provide a composition comprising the compound of anyof the aforementioned embodiments or salt thereof and at least one of apharmaceutically acceptable carrier or diluent. In certain embodiments,the composition has a viscosity less than about 40 centipoise (cP), lessthan about 30 centipose (cP), less than about 20 centipose (cP), lessthan about 15 centipose (cP), or less than about 10 centipose (cP). Incertain embodiments, the composition having any of the aforementionedviscosities comprises a compound provided herein at a concentration ofabout 100 mg/mL, about 125 mg/mL, about 150 mg/mL, about 175 mg/mL,about 200 mg/mL, about 225 mg/mL, about 250 mg/mL, about 275 mg/mL, orabout 300 mg/mL. In certain embodiments, the composition having any ofthe aforementioned viscosities and/or compound concentrations has atemperature of room temperature or about 20° C., about 21° C., about 22°C., about 23° C., about 24° C., about 25° C., about 26° C., about 27°C., about 28° C., about 29° C., or about 30° C.

Non-limiting numbered embodiments include:

E1. A compound comprising a modified oligonucleotide 8 to 80 linkednucleosides in length and having a nucleobase sequence comprising atleast 8 contiguous nucleobases of any of the nucleobase sequences of SEQID NOs: 2-10.

E2. A compound comprising a modified oligonucleotide 9 to 80 linkednucleosides in length and having a nucleobase sequence comprising atleast 9 contiguous nucleobases of any of the nucleobase sequences of SEQID NOs: 2-10.

E3. A compound comprising a modified oligonucleotide 10 to 80 linkednucleosides in length and having a nucleobase sequence comprising atleast 10 contiguous nucleobases of any of the nucleobase sequences ofSEQ ID NOs: 2-10.

E4. A compound comprising a modified oligonucleotide 11 to 80 linkednucleosides in length and having a nucleobase sequence comprising atleast 11 contiguous nucleobases of any of the nucleobase sequences ofSEQ ID NOs: 2-10.

E5. A compound comprising a modified oligonucleotide 12 to 80 linkednucleosides in length and having a nucleobase sequence comprising atleast 12 contiguous nucleobases of any of the nucleobase sequences ofSEQ ID NOs: 2-10.

E6. A compound comprising a modified oligonucleotide 16 to 80 linkednucleosides in length and having a nucleobase sequence comprising thenucleobase sequence of any one of SEQ ID NOs: 2-10.

E7. A compound comprising a modified oligonucleotide 16 linkednucleosides in length and having a nucleobase sequence consisting of anyone of SEQ ID NOs: 2-10.

E8. A compound comprising a modified oligonucleotide 8 to 80 linkednucleosides in length and complementary within nucleotides 1535-1550,2034-2049, 2341-2356, 4821-4836, 4840-4855, 4931-4946, 5049-5064,5494-5509, or 5495-5510 of SEQ ID NO: 1.

E9. The compound of any one of embodiments E1-E8, wherein the modifiedoligonucleotide comprises at least one modified internucleoside linkage,at least one modified sugar, or at least one modified nucleobase.

E10. The compound of embodiment E9, wherein the modified internucleosidelinkage is a phosphorothioate internucleoside linkage.

E11. The compound of embodiments E9 or E10, wherein the modified sugaris a bicyclic sugar.

E12. The compound of embodiment E11, wherein the bicyclic sugar isselected from the group consisting of: 4′-(CH₂)—O-2′ (LNA);4′-(CH₂)₂—O-2′ (ENA); and 4′-CH(CH₃)—O-2′ (cEt).

E13. The compound of embodiments E9 or E10, wherein the modified sugaris 2′-O-methoxyethyl.

E14. The compound of any one of embodiments E9-E13, wherein the modifiednucleobase is a 5-methylcytosine.

E15. The compound of any one of embodiments E1-E14, wherein the modifiedoligonucleotide comprises:

a gap segment consisting of linked 2′-deoxynucleosides;

a 5′ wing segment consisting of linked nucleosides; and

a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment and wherein each nucleoside of each wing segmentcomprises a modified sugar.

E16. A compound comprising a modified oligonucleotide 16 to 80 linkednucleosides in length and having a nucleobase sequence comprising anyone of SEQ ID NOs: 2-10, wherein the modified oligonucleotide comprises:

-   -   a gap segment consisting of linked 2′-deoxynucleosides;    -   a 5′ wing segment consisting of linked nucleosides; and    -   a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment and wherein each nucleoside of each wing segmentcomprises a modified sugar.

E17. A compound comprising a modified oligonucleotide 16-80 linkednucleobases in length having a nucleobase sequence comprising thesequence recited in any one of SEQ ID NOs: 2-7, wherein the modifiedoligonucleotide comprises:

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment; wherein each nucleoside of each wing segmentcomprises a cEt nucleoside; wherein each internucleoside linkage is aphosphorothioate linkage; and wherein each cytosine is a5-methylcytosine.

E18. The compound of any one of embodiments E1-E17, wherein theoligonucleotide is at least 80%, 85%, 90%, 95% or 100% complementary toSEQ ID NO: 1.

E19. The compound of any one of embodiments E1-E18, wherein the compoundis single-stranded.

E20. The compound of any one of embodiments E1-E18, wherein the compoundis double-stranded.

E21. The compound of any one of embodiments E1-E20, wherein the compoundcomprises ribonucleotides.

E22. The compound of any one of embodiments E1-E20, wherein the compoundcomprises deoxyribonucleotides.

E23. The compound of any one of embodiments E1-E22, wherein the modifiedoligonucleotide consists of 16 to 30 linked nucleosides.

E24. The compound of any preceding embodiments, wherein the compoundconsists of the modified oligonucleotide.

E25. A compound consisting of a pharmaceutically acceptable salt of anyof the compounds of embodiments E1-E24.

E26. The compound of embodiment 25, wherein the pharmaceuticallyacceptable salt is a sodium salt.

E27. The compound of embodiment 26, wherein the pharmaceuticallyacceptable salt is a potassium salt.

E28. A modified oligonucleotide according to the following chemicalstructure:

or a salt thereof.

E29. The modified oligonucleotide of embodiment E28, wherein themodified oligonucleotide is the sodium salt or the potassium salt.

E30. A modified oligonucleotide according to the following chemicalstructure:

E31. A composition comprising the compound of any one of embodimentsE1-E27 or the modified oligonucleotide of any one of embodiments E28-E30and a pharmaceutically acceptable diluent or carrier.

E32. A composition comprising the compound of any one of embodimentsE1-E27 or the modified oligonucleotide of any one of embodiments E28-E30and water.

E33. A composition comprising the compound of any one of embodimentsE1-E27 or the modified oligonucleotide of any one of embodiments E28-E30for use in therapy.

E34. A method of treating or ameliorating cancer in an individualcomprising administering to the individual a compound targeted toMALAT1, thereby treating or ameliorating the cancer.

E35. The method of embodiment E34, wherein the compound is an antisensecompound targeted to MALAT1.

E36. The method of embodiments E34 or E35, wherein the cancer is breastcancer; inflammatory breast cancer; breast ductal carcinoma; breastlobular carcinoma; luminal A breast cancer; luminal B breast cancer;basal-like breast cancer; HER2 positive (HER2+) breast cancer; HER2negative (HER2−) breast cancer; Estrogen Receptor negative (ER−) breastcancer; Estrogen Receptor positive (ER+) breast cancer; ProgesteroneReceptor negative (PR−) breast cancer; Progesterone Receptor positive(PR+) breast cancer; ER positive (ER+) and PR positive (PR+) breastcancer; ER positive (ER+) and PR negative (PR−) breast cancer; ERnegative (ER−) and PR positive (PR+) breast cancer; ER positive (ER+)and HER2 negative (HER2−) breast cancer; ER−, PR−, and HER2− triplenegative breast cancer (ER−, PR−, HER2−; TNBC); hormone receptornegative breast cancer (ER− and PR−); ER+, PR+, and HER2+ triplepositive breast cancer (ER+, PR+, HER2+; TPBC); hepatocellular carcinoma(HCC); head and neck squamous cell carcinoma (HNSCC); oral tonguesquamous cell carcinoma (OTSCC); sarcomas (e.g. epitheloid, rhabdoid andsynovial); esophageal cancer; gastric cancer; ovarian cancer; pancreaticcancer; lung cancer; non-small cell lung carcinoma (NSCLC); small-celllung carcinoma (SCLC); squamous cell carcinoma (SCC); head and neckcancer; head and neck squamous cell carcinoma (HNSCC); gastrointestinalcancer; large intestinal cancer; small intestinal cancer; stomachcancer; colon cancer; colorectal cancer; bladder cancer; liver cancer;biliary tract cancer; urothelial cancer; endometrial cancer; cervicalcancer; prostate cancer; mesothelioma; chordoma; renal cancer; renalcell carcinoma (RCC); brain cancer; neuroblastoma; glioblastoma; skincancer; melanoma; basal cell carcinoma; merkel cell carcinoma; bloodcancer; hematopoetic cancer; myeloma; multiple myeloma (MM); B cellmalignancies; lymphoma; B cell lymphoma; Hodgkin lymphoma; T celllymphoma; leukemia; or acute lymphocytic leukemia (ALL).

E37. The method of any of embodiments E34-E36, wherein administering thecompound inhibits or reduces cancer cell proliferation, cancer cellmigration, cancer cell branching morphogenesis, tumor progression, tumorgrowth, or metastasis.

E38. The method of any of embodiments E34-E37, wherein administering thecompound increases or induces cancer cell differentiation, cancer celladhesion, or tumor differentiation.

E39. The method of any of embodiments E34-E38, wherein administering thecompound induces a cancer cell or tumor to have a cystic, ductular, oracinar phenotype or morphology.

E40. The method of any of embodiments E34-E39, wherein administering thecompound induces a cancer cell or tumor to have a more differentiatedphenotype or structure.

E41. The method of embodiment E40, wherein the more differentiatedphenotype or structure comprises presence of secretory lipid droplets,increased desmosomal structures, polarized ductal structures, orincreased levels of E-cadherin or casein.

E42. A method of inhibiting expression of MALAT1 in a cancer cellcomprising contacting the cancer cell with a compound targeted toMALAT1, thereby inhibiting expression of MALAT1 in the cancer cell.

E43. The method of embodiment E42, wherein the cancer is breast cancer;inflammatory breast cancer; breast ductal carcinoma; breast lobularcarcinoma; luminal A breast cancer; luminal B breast cancer; basal-likebreast cancer; HER2 positive (HER2+) breast cancer; HER2 negative(HER2−) breast cancer; Estrogen Receptor negative (ER−) breast cancer;Estrogen Receptor positive (ER+) breast cancer; Progesterone Receptornegative (PR−) breast cancer; Progesterone Receptor positive (PR+)breast cancer; ER positive (ER+) and PR positive (PR+) breast cancer; ERpositive (ER+) and PR negative (PR−) breast cancer; ER negative (ER−)and PR positive (PR+) breast cancer; ER positive (ER+) and HER2 negative(HER2−) breast cancer; ER−, PR−, and HER2− triple negative breast cancer(ER−, PR−, HER2−; TNBC); hormone receptor negative breast cancer (ER−and PR−); ER+, PR+, and HER2+ triple positive breast cancer (ER+, PR+,HER2+; TPBC); hepatocellular carcinoma (HCC); head and neck squamouscell carcinoma (HNSCC); oral tongue squamous cell carcinoma (OTSCC);sarcomas (e.g. epitheloid, rhabdoid and synovial); esophageal cancer;gastric cancer; ovarian cancer; pancreatic cancer; lung cancer;non-small cell lung carcinoma (NSCLC); small-cell lung carcinoma (SCLC);squamous cell carcinoma (SCC); head and neck cancer; head and necksquamous cell carcinoma (HNSCC); gastrointestinal cancer; largeintestinal cancer; small intestinal cancer; stomach cancer; coloncancer; colorectal cancer; bladder cancer; liver cancer; biliary tractcancer; urothelial cancer; endometrial cancer; cervical cancer; prostatecancer; mesothelioma; chordoma; renal cancer; renal cell carcinoma(RCC); brain cancer; neuroblastoma; glioblastoma; skin cancer; melanoma;basal cell carcinoma; merkel cell carcinoma; blood cancer; hematopoeticcancer; myeloma; multiple myeloma (MM); B cell malignancies; lymphoma; Bcell lymphoma; Hodgkin lymphoma; T cell lymphoma; leukemia; or acutelymphocytic leukemia (ALL).

E44. A method of reducing or inhibiting cancer cell proliferation,cancer cell migration, cancer cell branching morphogenesis, tumorprogression, tumor growth, or metastasis in an individual having cancercomprising administering a compound targeted to MALAT1 to theindividual, thereby reducing or inhibiting cancer cell proliferation,cancer cell migration, cancer cell branching morphogenesis, tumorprogression, tumor growth, or metastasis in the individual.

E45. A method of increasing or inducing cancer cell differentiation,cancer cell adhesion, or tumor differentiation in an individual havingcancer comprising administering a compound targeted to MALAT1 to theindividual, thereby increasing or inducing cancer cell differentiation,cancer cell adhesion, or tumor differentiation in the individual.

E46. A method of inducing a cancer cell or tumor to have a cystic,ductular, or acinar phenotype or morphology in an individual havingcancer comprising administering a compound targeted to MALAT1 to theindividual, thereby inducing the cancer cell or tumor to have a cystic,ductular, or acinar phenotype or morphology.

E47. A method of inducing a cancer cell or tumor to have a moredifferentiated phenotype or structure comprising administering acompound targeted to MALAT1 to the individual, thereby inducing thecancer cell or tumor to have a more differentiated phenotype orstructure.

E48. The method of embodiment E47, wherein the more differentiatedphenotype or structure comprises presence of secretory lipid droplets,increased desmosomal structures, polarized ductal structures, orincreased levels of E-cadherin or casein.

E49. The method of any of embodiments E44-E48, wherein the individualhas breast cancer; inflammatory breast cancer; breast ductal carcinoma;breast lobular carcinoma; luminal A breast cancer; luminal B breastcancer; basal-like breast cancer; HER2 positive (HER2+) breast cancer;HER2 negative (HER2−) breast cancer; Estrogen Receptor negative (ER−)breast cancer; Estrogen Receptor positive (ER+) breast cancer;Progesterone Receptor negative (PR−) breast cancer; ProgesteroneReceptor positive (PR+) breast cancer; ER positive (ER+) and PR positive(PR+) breast cancer; ER positive (ER+) and PR negative (PR−) breastcancer; ER negative (ER−) and PR positive (PR+) breast cancer; ERpositive (ER+) and HER2 negative (HER2−) breast cancer; ER−, PR−, andHER2− triple negative breast cancer (ER−, PR−, HER2−; TNBC); hormonereceptor negative breast cancer (ER− and PR−); ER+, PR+, and HER2+triple positive breast cancer (ER+, PR+, HER2+; TPBC); hepatocellularcarcinoma (HCC); head and neck squamous cell carcinoma (HNSCC); oraltongue squamous cell carcinoma (OTSCC); sarcomas (e.g. epitheloid,rhabdoid and synovial); esophageal cancer; gastric cancer; ovariancancer; pancreatic cancer; lung cancer; non-small cell lung carcinoma(NSCLC); small-cell lung carcinoma (SCLC); squamous cell carcinoma(SCC); head and neck cancer; head and neck squamous cell carcinoma(HNSCC); gastrointestinal cancer; large intestinal cancer; smallintestinal cancer; stomach cancer; colon cancer; colorectal cancer;bladder cancer; liver cancer; biliary tract cancer; urothelial cancer;endometrial cancer; cervical cancer; prostate cancer; mesothelioma;chordoma; renal cancer; renal cell carcinoma (RCC); brain cancer;neuroblastoma; glioblastoma; skin cancer; melanoma; basal cellcarcinoma; merkel cell carcinoma; blood cancer; hematopoetic cancer;myeloma; multiple myeloma (MM); B cell malignancies; lymphoma; B celllymphoma; Hodgkin lymphoma; T cell lymphoma; leukemia; or acutelymphocytic leukemia (ALL).

E50. The method of any one of embodiments E34-E49, wherein the compoundis an antisense compound targeted to MALAT1.

E51. The method of any one of embodiments E34-E49, wherein the compoundis the compound of any one of embodiments E1-E27, the modifiedoligonucleotide of any one of embodiments E28-E30, or the composition ofembodiment E31 or E32.

E52. The method of any of embodiments E34-E51, wherein the compound isadministered parenterally.

E53. Use of a compound targeted to MALAT1 for treating, preventing, orameliorating a cancer associated with MALAT1.

E54. The use of embodiment E53, wherein the cancer is breast cancer;inflammatory breast cancer; breast ductal carcinoma; breast lobularcarcinoma; luminal A breast cancer; luminal B breast cancer; basal-likebreast cancer; HER2 positive (HER2+) breast cancer; HER2 negative(HER2−) breast cancer; Estrogen Receptor negative (ER−) breast cancer;Estrogen Receptor positive (ER+) breast cancer; Progesterone Receptornegative (PR−) breast cancer; Progesterone Receptor positive (PR+)breast cancer; ER positive (ER+) and PR positive (PR+) breast cancer; ERpositive (ER+) and PR negative (PR−) breast cancer; ER negative (ER−)and PR positive (PR+) breast cancer; ER positive (ER+) and HER2 negative(HER2−) breast cancer; ER−, PR−, and HER2− triple negative breast cancer(ER−, PR−, HER2−; TNBC); hormone receptor negative breast cancer (ER−and PR−); ER+, PR+, and HER2+ triple positive breast cancer (ER+, PR+,HER2+; TPBC); hepatocellular carcinoma (HCC); head and neck squamouscell carcinoma (HNSCC); oral tongue squamous cell carcinoma (OTSCC);sarcomas (e.g. epitheloid, rhabdoid and synovial); esophageal cancer;gastric cancer; ovarian cancer; pancreatic cancer; lung cancer;non-small cell lung carcinoma (NSCLC); small-cell lung carcinoma (SCLC);squamous cell carcinoma (SCC); head and neck cancer; head and necksquamous cell carcinoma (HNSCC); gastrointestinal cancer; largeintestinal cancer; small intestinal cancer; stomach cancer; coloncancer; colorectal cancer; bladder cancer; liver cancer; biliary tractcancer; urothelial cancer; endometrial cancer; cervical cancer; prostatecancer; mesothelioma; chordoma; renal cancer; renal cell carcinoma(RCC); brain cancer; neuroblastoma; glioblastoma; skin cancer; melanoma;basal cell carcinoma; merkel cell carcinoma; blood cancer; hematopoeticcancer; myeloma; multiple myeloma (MM); B cell malignancies; lymphoma; Bcell lymphoma; Hodgkin lymphoma; T cell lymphoma; leukemia; or acutelymphocytic leukemia (ALL).

E55. The use of embodiment E53 or E54, wherein the compound is anantisense compound targeted to MALAT1.

E56. The use of any one of embodiments E53-E55, wherein the compound isthe compound of any one of embodiments E1-E27, the modifiedoligonucleotide of any one of embodiments E28-E30, or the composition ofembodiment E31 or E32.

E57. Use of a compound targeted to MALAT1 in the manufacture of amedicament for treating or ameliorating a cancer associated with MALAT1.

E58. The use of embodiment E57, wherein the cancer is breast cancer;inflammatory breast cancer; breast ductal carcinoma; breast lobularcarcinoma; luminal A breast cancer; luminal B breast cancer; basal-likebreast cancer; HER2 positive (HER2+) breast cancer; HER2 negative(HER2−) breast cancer; Estrogen Receptor negative (ER−) breast cancer;Estrogen Receptor positive (ER+) breast cancer; Progesterone Receptornegative (PR−) breast cancer; Progesterone Receptor positive (PR+)breast cancer; ER positive (ER+) and PR positive (PR+) breast cancer; ERpositive (ER+) and PR negative (PR−) breast cancer; ER negative (ER−)and PR positive (PR+) breast cancer; ER positive (ER+) and HER2 negative(HER2−) breast cancer; ER−, PR−, and HER2− triple negative breast cancer(ER−, PR−, HER2−; TNBC); hormone receptor negative breast cancer (ER−and PR−); ER+, PR+, and HER2+ triple positive breast cancer (ER+, PR+,HER2+; TPBC); hepatocellular carcinoma (HCC); head and neck squamouscell carcinoma (HNSCC); oral tongue squamous cell carcinoma (OTSCC);sarcomas (e.g. epitheloid, rhabdoid and synovial); esophageal cancer;gastric cancer; ovarian cancer; pancreatic cancer; lung cancer;non-small cell lung carcinoma (NSCLC); small-cell lung carcinoma (SCLC);squamous cell carcinoma (SCC); head and neck cancer; head and necksquamous cell carcinoma (HNSCC); gastrointestinal cancer; largeintestinal cancer; small intestinal cancer; stomach cancer; coloncancer; colorectal cancer; bladder cancer; liver cancer; biliary tractcancer; urothelial cancer; endometrial cancer; cervical cancer; prostatecancer; mesothelioma; chordoma; renal cancer; renal cell carcinoma(RCC); brain cancer; neuroblastoma; glioblastoma; skin cancer; melanoma;basal cell carcinoma; merkel cell carcinoma; blood cancer; hematopoeticcancer; myeloma; multiple myeloma (MM); B cell malignancies; lymphoma; Bcell lymphoma; Hodgkin lymphoma; T cell lymphoma; leukemia; or acutelymphocytic leukemia (ALL).

E59. The use of embodiment E57 or E58, wherein the compound is anantisense compound targeted to MALAT1.

E60. The use of any one of embodiments E57-E59, wherein the compound isthe compound of any one of embodiments E1-E27, the modifiedoligonucleotide of any one of embodiments E28-E30, or the composition ofembodiment E31 or E32.

E61. Use of a compound targeted to MALAT1 in the preparation of amedicament for treating or ameliorating a cancer associated with MALAT1.

E62. The use of embodiment E61, wherein the cancer is breast cancer;inflammatory breast cancer; breast ductal carcinoma; breast lobularcarcinoma; luminal A breast cancer; luminal B breast cancer; basal-likebreast cancer; HER2 positive (HER2+) breast cancer; HER2 negative(HER2−) breast cancer; Estrogen Receptor negative (ER−) breast cancer;Estrogen Receptor positive (ER+) breast cancer; Progesterone Receptornegative (PR−) breast cancer; Progesterone Receptor positive (PR+)breast cancer; ER positive (ER+) and PR positive (PR+) breast cancer; ERpositive (ER+) and PR negative (PR−) breast cancer; ER negative (ER−)and PR positive (PR+) breast cancer; ER positive (ER+) and HER2 negative(HER2−) breast cancer; ER−, PR−, and HER2− triple negative breast cancer(ER−, PR−, HER2−; TNBC); hormone receptor negative breast cancer (ER−and PR−); ER+, PR+, and HER2+ triple positive breast cancer (ER+, PR+,HER2+; TPBC); hepatocellular carcinoma (HCC); head and neck squamouscell carcinoma (HNSCC); oral tongue squamous cell carcinoma (OTSCC);sarcomas (e.g. epitheloid, rhabdoid and synovial); esophageal cancer;gastric cancer; ovarian cancer; pancreatic cancer; lung cancer;non-small cell lung carcinoma (NSCLC); small-cell lung carcinoma (SCLC);squamous cell carcinoma (SCC); head and neck cancer; head and necksquamous cell carcinoma (HNSCC); gastrointestinal cancer; largeintestinal cancer; small intestinal cancer; stomach cancer; coloncancer; colorectal cancer; bladder cancer; liver cancer; biliary tractcancer; urothelial cancer; endometrial cancer; cervical cancer; prostatecancer; mesothelioma; chordoma; renal cancer; renal cell carcinoma(RCC); brain cancer; neuroblastoma; glioblastoma; skin cancer; melanoma;basal cell carcinoma; merkel cell carcinoma; blood cancer; hematopoeticcancer; myeloma; multiple myeloma (MM); B cell malignancies; lymphoma; Bcell lymphoma; Hodgkin lymphoma; T cell lymphoma; leukemia; or acutelymphocytic leukemia (ALL).

E63. The use of embodiment E61 or E62, wherein the compound is anantisense compound targeted to MALAT1.

E64. The use of any one of embodiments E61-E63, wherein the compound isthe compound of any one of embodiments E1-E27, the modifiedoligonucleotide of any one of embodiments E28-E30, or the composition ofembodiment E31 or E32.

Certain Indications

Certain embodiments provided herein relate to methods of inhibitingMALAT1 expression, which can be useful for treating, preventing, orameliorating a cancer associated with MALAT1 in an individual, byadministration of a compound that targets MALAT1. In certainembodiments, the compound can be a MALAT1 specific inhibitor. In certainembodiments, the compound can be an antisense compound, oligomericcompound, or oligonucleotide targeted to MALAT1.

Examples of cancers associated with MALAT1 treatable, preventable,and/or ameliorable with the compounds and methods provided hereininclude breast cancer; inflammatory breast cancer; breast ductalcarcinoma; breast lobular carcinoma; luminal A breast cancer; luminal Bbreast cancer; basal-like breast cancer; HER2 positive (HER2+) breastcancer; HER2 negative (HER2−) breast cancer; Estrogen Receptor negative(ER−) breast cancer; Estrogen Receptor positive (ER+) breast cancer;Progesterone Receptor negative (PR−) breast cancer; ProgesteroneReceptor positive (PR+) breast cancer; ER positive (ER+) and PR positive(PR+) breast cancer; ER positive (ER+) and PR negative (PR−) breastcancer; ER negative (ER−) and PR positive (PR+) breast cancer; ERpositive (ER+) and HER2 negative (HER2−) breast cancer; ER−, PR−, andHER2− triple negative breast cancer (ER−, PR−, HER2−; TNBC); hormonereceptor negative breast cancer (ER− and PR−); ER+, PR+, and HER2+triple positive breast cancer (ER+, PR+, HER2+; TPBC); hepatocellularcarcinoma (HCC); head and neck squamous cell carcinoma (HNSCC); oraltongue squamous cell carcinoma (OTSCC); sarcomas (e.g. epitheloid,rhabdoid and synovial); esophageal cancer; gastric cancer; ovariancancer; pancreatic cancer; lung cancer; non-small cell lung carcinoma(NSCLC); small-cell lung carcinoma (SCLC); squamous cell carcinoma(SCC); head and neck cancer; head and neck squamous cell carcinoma(HNSCC); gastrointestinal cancer; large intestinal cancer; smallintestinal cancer; stomach cancer; colon cancer; colorectal cancer;bladder cancer; liver cancer; biliary tract cancer; urothelial cancer;endometrial cancer; cervical cancer; prostate cancer; mesothelioma;chordoma; renal cancer; renal cell carcinoma (RCC); brain cancer;neuroblastoma; glioblastoma; skin cancer; melanoma; basal cellcarcinoma; merkel cell carcinoma; blood cancer; hematopoetic cancer;myeloma; multiple myeloma (MM); B cell malignancies; lymphoma; B celllymphoma; Hodgkin lymphoma; T cell lymphoma; leukemia; or acutelymphocytic leukemia (ALL).

In certain embodiments, the breast cancer has one or more of thefollowing characteristics: Androgen Receptor positive, dependent onandrogen for growth; Estrogen Receptor (ER) negative, independent ofestrogen for growth; Progesterone Receptor (PR) negative, independent ofprogesterone for growth; or Her2/neu negative. In certain embodiments,the breast cancer is ER, PR, and HER2 triple negative (ER−, PR−, HER2−).In certain embodiments, the breast cancer is triple negative and ARpositive (ER−, PR−, HER2−, AR+). In certain embodiments, the breastcancer is ER negative and AR positive (ER−, AR+). In certainembodiments, the breast cancer is ER positive and AR positive (ER+,AR+). In certain embodiments, the breast cancer is apocrine. Apocrinebreast cancers are often “triple negative”, meaning that the cells donot express ER, PR, or HER2 receptors, and usually, but not necessarily,AR positive. In certain embodiments, an apocrine breast cancer is ER,PR, and HER2 triple negative and AR positive (ER−, PR−, HER2−, AR+). Incertain embodiments, an apocrine breast cancer is ER negative and ARpositive (ER−, AR+). In certain embodiments, an apocrine breast canceroriginates from the sweat gland of the breast. In certain embodiments,an apocrine breast cancer is a ductal cancer or cancer cell of thebreast. In certain embodiments, an apocrine breast cancer can have anyone or more of the following features: a large amount of eosinophilicgranular cytoplasm, well-defined margins, large vesicular nuclei, anuclear to cytoplasmic ratio of about 1:2, and/or accumulations ofsecreted granules in the apical cytoplasm known as apical snouts. Incertain embodiments, the breast cancer is an ER negative and AR positive(ER−, AR+) molecular apocrine breast cancer. In certain aspects, an ERnegative and AR positive (ER−, AR+) molecular apocrine breast cancer canfurther be PR positive, PR negative, HER2 negative, or HER2 positive. Incertain embodiments, the breast cancer is HER2 positive. In certainembodiments, the breast cancer is PR positive. In certain embodiments,the breast cancer is ER positive. Breast cancer can be identified aspositive or negative with respect to hormone receptors, such as ER, PR,or HER2 by standard histological techniques. For example, in someembodiments histological breast cancer samples can be classified as“triple negative” (ER−, PR−, HER2−) when less than 1% of cellsdemonstrate nuclear staining for estrogen and progesterone receptors,and immunohistochemical staining for HER2 shows a 0, 1-fold, or a 2-foldpositive score and a FISH ratio (HER2 gene signals to chromosome 17signals) of less than 1.8 according to the relevant ASCO and CAPguidelines. (Meyer, P. et al., PLoS ONE 7(5): e38361 (2012)).

In certain embodiments, the B-cell lymphoma is a non-Hodgkin's B-celllymphoma. Examples of non-Hodgkin's B-cell lymphoma of certainembodiments that can be treated with compounds provided herein include,but are not limited to, diffuse large B cell lymphoma (DLBCL), activatedB-cell lymphoma (ABC-DLBCL), germinal center B-cell lymphoma (GCBDLBCL), follicular lymphoma, mucosa-associated lymphatic tissue lymphoma(MALT), small cell lymphocytic lymphoma, chronic lymphocytic leukemia,mantle cell lymphoma (MCL), Burkitt lymphoma, mediastinal large B celllymphoma, Waldenstrom macroglobulinemia, nodal marginal zone B celllymphoma (NMZL), splenic marginal zone lymphoma (SMZL), intravascularlarge B-cell lymphoma, primary effusion lymphoma, and lymphomatoidgranulomatosis.

In certain embodiments, the T-cell lymphoma that can be treated withcompounds provided herein include, but are not limited to, peripheralT-cell lymphoma, and anaplastic large cell lymphoma (ALCL).

In certain embodiments, the leukemia that can be treated with compoundsprovided herein includes, but is not limited to, acute lymphocyticleukemia (ALL).

In certain embodiments, a method of treating, preventing, orameliorating a cancer associated with MALAT1 in an individual comprisesadministering to the individual a compound comprising a MALAT1 specificinhibitor, thereby treating, preventing, or ameliorating the cancer. Incertain embodiments, the compound comprises an antisense compoundtargeted to MALAT1. In certain embodiments, the compound comprises anoligonucleotide targeted to MALAT1. In certain embodiments, a compoundcomprises a modified oligonucleotide consisting of 8 to 80 linkednucleosides and having a nucleobase sequence comprising at least 8contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs:2-10. In certain embodiments, a compound comprises a modifiedoligonucleotide consisting of 16 to 80 linked nucleosides and having anucleobase sequence comprising the nucleobase sequence of any one of SEQID NOs: 2-10. In certain embodiments, a compound comprises a modifiedoligonucleotide consisting of the nucleobase sequence of any one of SEQID NOs: 2-10. In certain embodiments, a compound comprises a modifiedoligonucleotide consisting of 8 to 80 linked nucleosides and having anucleobase sequence comprising at least 8 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 36-2646 or 2664-2813. Incertain embodiments, a compound comprises a modified oligonucleotideconsisting of 16 to 80 linked nucleosides and having a nucleobasesequence comprising the nucleobase sequence of any one of SEQ ID NOs:36-2646 or 2664-2813. In certain embodiments, a compound comprises amodified oligonucleotide consisting of the nucleobase sequence of anyone of SEQ ID NOs: SEQ ID NOs: 36-2646 or 2664-2813. In any of theforegoing embodiments, the modified oligonucleotide can consist of 10 to30 linked nucleosides. In certain embodiments, the compound is ION1157034, 1157111, 1157190, 1157929, 1158161, 1158162, 1304884, 1304890,or 1304906. In any of the foregoing embodiments, the compound can besingle-stranded or double-stranded. In any of the foregoing embodiments,the compound can be an antisense compound or oligomeric compound. Incertain embodiments, the compound is administered to the individualparenterally. In certain embodiments, administering the compoundinhibits or reduces cancer cell proliferation, cancer cell migration,cancer cell branching morphogenesis, tumor progression, tumor growth, ormetastasis. In certain embodiments, administering the compound increasesor induces cancer cell differentiation, cancer cell adhesion, or tumordifferentiation. In certain embodiments, administering the compoundinduces a breast cancer cell or breast tumor to have a cystic, ductular,or acinar phenotype or morphology. In certain embodiments, administeringthe compound induces a breast cancer cell or breast tumor to have a moredifferentiated phenotype or structure. In certain embodiments, the moredifferentiated phenotype or structure includes, but is not limited to,presence of secretory lipid droplets, increased desmosomal structures,polarized ductal structures, or increased levels of differentiationmarkers such as E-cadherin or milk proteins such as casein.

In certain embodiments, a method of treating or ameliorating cancercomprises administering to the individual a compound comprising a MALAT1specific inhibitor, thereby treating or ameliorating the cancer. Incertain embodiments, the cancer is breast cancer; inflammatory breastcancer; breast ductal carcinoma; breast lobular carcinoma; luminal Abreast cancer; luminal B breast cancer; basal-like breast cancer; HER2positive (HER2+) breast cancer; HER2 negative (HER2−) breast cancer;Estrogen Receptor negative (ER−) breast cancer; Estrogen Receptorpositive (ER+) breast cancer; Progesterone Receptor negative (PR−)breast cancer; Progesterone Receptor positive (PR+) breast cancer; ERpositive (ER+) and PR positive (PR+) breast cancer; ER positive (ER+)and PR negative (PR−) breast cancer; ER negative (ER−) and PR positive(PR+) breast cancer; ER positive (ER+) and HER2 negative (HER2−) breastcancer; ER−, PR−, and HER2− triple negative breast cancer (ER−, PR−,HER2−; TNBC); hormone receptor negative breast cancer (ER− and PR−);ER+, PR+, and HER2+ triple positive breast cancer (ER+, PR+, HER2+;TPBC); hepatocellular carcinoma (HCC); head and neck squamous cellcarcinoma (HNSCC); oral tongue squamous cell carcinoma (OTSCC); sarcomas(e.g. epitheloid, rhabdoid and synovial); esophageal cancer; gastriccancer; ovarian cancer; pancreatic cancer; lung cancer; non-small celllung carcinoma (NSCLC); small-cell lung carcinoma (SCLC); squamous cellcarcinoma (SCC); head and neck cancer; head and neck squamous cellcarcinoma (HNSCC); gastrointestinal cancer; large intestinal cancer;small intestinal cancer; stomach cancer; colon cancer; colorectalcancer; bladder cancer; liver cancer; biliary tract cancer; urothelialcancer; endometrial cancer; cervical cancer; prostate cancer;mesothelioma; chordoma; renal cancer; renal cell carcinoma (RCC); braincancer; neuroblastoma; glioblastoma; skin cancer; melanoma; basal cellcarcinoma; merkel cell carcinoma; blood cancer; hematopoetic cancer;myeloma; multiple myeloma (MM); B cell malignancies; lymphoma; B celllymphoma; Hodgkin lymphoma; T cell lymphoma; leukemia; or acutelymphocytic leukemia (ALL). In certain embodiments, the compoundcomprises an antisense compound targeted to MALAT1. In certainembodiments, the compound comprises an oligonucleotide targeted toMALAT1. In certain embodiments, the compound comprises a modifiedoligonucleotide consisting of 8 to 80 linked nucleosides and having anucleobase sequence comprising at least 8 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 2-10. In certain embodiments,the compound comprises a modified oligonucleotide consisting of 16 to 80linked nucleosides and having a nucleobase sequence comprising thenucleobase sequence of any one of SEQ ID NOs: 2-10. In certainembodiments, the compound comprises a modified oligonucleotideconsisting of the nucleobase sequence of any one of SEQ ID NOs: 2-10. Incertain embodiments, a compound comprises a modified oligonucleotideconsisting of 8 to 80 linked nucleosides and having a nucleobasesequence comprising at least 8 contiguous nucleobases of any of thenucleobase sequences of SEQ ID NOs: 36-2646 or 2664-2813. In certainembodiments, a compound comprises a modified oligonucleotide consistingof 16 to 80 linked nucleosides and having a nucleobase sequencecomprising the nucleobase sequence of any one of SEQ ID NOs: 36-2646 or2664-2813. In certain embodiments, a compound comprises a modifiedoligonucleotide consisting of the nucleobase sequence of any one of SEQID NOs: SEQ ID NOs: 36-2646 or 2664-2813. In any of the foregoingembodiments, the modified oligonucleotide can consist of 10 to 30 linkednucleosides. In certain embodiments, the compound is ION 1157034,1157111, 1157190, 1157929, 1158161, 1158162, 1304884, 1304890, or1304906. In any of the foregoing embodiments, the compound can besingle-stranded or double-stranded. In any of the foregoing embodiments,the compound can be an antisense compound or oligomeric compound. Incertain embodiments, the compound is administered to the individualparenterally. In certain embodiments, administering the compoundinhibits or reduces cancer cell proliferation, cancer cell migration,cancer cell branching morphogenesis, tumor progression, tumor growth, ormetastasis. In certain embodiments, administering the compound increasesor induces cancer cell differentiation, cancer cell adhesion, or tumordifferentiation. In certain embodiments, administering the compoundinduces a breast cancer cell or breast tumor to have a cystic, ductular,or acinar phenotype or morphology. In certain embodiments, administeringthe compound induces a breast cancer cell or breast tumor to have a moredifferentiated phenotype or structure. In certain embodiments, the moredifferentiated phenotype or structure includes, but is not limited to,presence of secretory lipid droplets, increased desmosomal structures,polarized ductal structures, or increased levels of differentiationmarkers such as E-cadherin or milk proteins such as casein.

In certain embodiments, the individual is identified as having or atrisk of having a cancer associated with MALAT1.

In certain embodiments, a method of inhibiting expression of MALAT1 inan individual having, or at risk of having, a cancer associated withMALAT1 comprises administering to the individual a compound comprising aMALAT1 specific inhibitor, thereby inhibiting expression of MALAT1 inthe individual. In certain embodiments, administering the compoundinhibits expression of MALAT1 in the breast. In certain embodiments, theindividual has, or is at risk of having breast cancer; inflammatorybreast cancer; breast ductal carcinoma; breast lobular carcinoma;luminal A breast cancer; luminal B breast cancer; basal-like breastcancer; HER2 positive (HER2+) breast cancer; HER2 negative (HER2−)breast cancer; Estrogen Receptor negative (ER−) breast cancer; EstrogenReceptor positive (ER+) breast cancer; Progesterone Receptor negative(PR−) breast cancer; Progesterone Receptor positive (PR+) breast cancer;ER positive (ER+) and PR positive (PR+) breast cancer; ER positive (ER+)and PR negative (PR−) breast cancer; ER negative (ER−) and PR positive(PR+) breast cancer; ER positive (ER+) and HER2 negative (HER2−) breastcancer; ER−, PR−, and HER2− triple negative breast cancer (ER−, PR−,HER2−; TNBC); hormone receptor negative breast cancer (ER− and PR−);ER+, PR+, and HER2+ triple positive breast cancer (ER+, PR+, HER2+;TPBC); hepatocellular carcinoma (HCC); head and neck squamous cellcarcinoma (HNSCC); oral tongue squamous cell carcinoma (OTSCC); sarcomas(e.g. epitheloid, rhabdoid and synovial); esophageal cancer; gastriccancer; ovarian cancer; pancreatic cancer; lung cancer; non-small celllung carcinoma (NSCLC); small-cell lung carcinoma (SCLC); squamous cellcarcinoma (SCC); head and neck cancer; head and neck squamous cellcarcinoma (HNSCC); gastrointestinal cancer; large intestinal cancer;small intestinal cancer; stomach cancer; colon cancer; colorectalcancer; bladder cancer; liver cancer; biliary tract cancer; urothelialcancer; endometrial cancer; cervical cancer; prostate cancer;mesothelioma; chordoma; renal cancer; renal cell carcinoma (RCC); braincancer; neuroblastoma; glioblastoma; skin cancer; melanoma; basal cellcarcinoma; merkel cell carcinoma; blood cancer; hematopoetic cancer;myeloma; multiple myeloma (MM); B cell malignancies; lymphoma; B celllymphoma; Hodgkin lymphoma; T cell lymphoma; leukemia; or acutelymphocytic leukemia (ALL). In certain embodiments, the compoundcomprises an antisense compound targeted to MALAT1. In certainembodiments, the compound comprises an oligonucleotide targeted toMALAT1. In certain embodiments, the compound comprises a modifiedoligonucleotide consisting of 8 to 80 linked nucleosides and having anucleobase sequence comprising at least 8 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 2-10. In certain embodiments,the compound comprises a modified oligonucleotide consisting of 16 to 80linked nucleosides and having a nucleobase sequence comprising thenucleobase sequence of any one of SEQ ID NOs: 2-10. In certainembodiments, the compound comprises a modified oligonucleotideconsisting of the nucleobase sequence of any one of SEQ ID NOs: 2-10. Incertain embodiments, a compound comprises a modified oligonucleotideconsisting of 8 to 80 linked nucleosides and having a nucleobasesequence comprising at least 8 contiguous nucleobases of any of thenucleobase sequences of SEQ ID NOs: 36-2646 or 2664-2813. In certainembodiments, a compound comprises a modified oligonucleotide consistingof 16 to 80 linked nucleosides and having a nucleobase sequencecomprising the nucleobase sequence of any one of SEQ ID NOs: 36-2646 or2664-2813. In certain embodiments, a compound comprises a modifiedoligonucleotide consisting of the nucleobase sequence of any one of SEQID NOs: SEQ ID NOs: 36-2646 or 2664-2813. In any of the foregoingembodiments, the modified oligonucleotide can consist of 10 to 30 linkednucleosides. In certain embodiments, the compound is ION 1157034,1157111, 1157190, 1157929, 1158161, 1158162, 1304884, 1304890, or1304906. In any of the foregoing embodiments, the compound can besingle-stranded or double-stranded. In any of the foregoing embodiments,the compound can be an antisense compound or oligomeric compound. Incertain embodiments, the compound is administered to the individualparenterally. In certain embodiments, administering the compoundinhibits or reduces cancer cell proliferation, cancer cell migration,cancer cell branching morphogenesis, tumor progression, tumor growth, ormetastasis. In certain embodiments, administering the compound increasesor induces cancer cell differentiation, cancer cell adhesion, or tumordifferentiation. In certain embodiments, administering the compoundinduces a breast cancer cell or breast tumor to have a cystic, ductular,or acinar phenotype or morphology. In certain embodiments, administeringthe compound induces a breast cancer cell or breast tumor to have a moredifferentiated phenotype or structure. In certain embodiments, the moredifferentiated phenotype or structure includes, but is not limited to,presence of secretory lipid droplets, increased desmosomal structures,polarized ductal structures, or increased levels of differentiationmarkers such as E-cadherin or milk proteins such as casein.

In certain embodiments, the individual is identified as having or atrisk of having a cancer associated with MALAT1.

In certain embodiments, a method of inhibiting expression of MALAT1 in acell comprises contacting the cell with a compound comprising a MALAT1specific inhibitor, thereby inhibiting expression of MALAT1 in the cell.In certain embodiments, the cell is a cancer cell. In certainembodiments, the cell is a breast cell. In certain embodiments, the cellis in the breast. In certain embodiments, the cell is in the breast ofan individual who has, or is at risk of having cancer, such as breastcancer; inflammatory breast cancer; breast ductal carcinoma; breastlobular carcinoma; luminal A breast cancer; luminal B breast cancer;basal-like breast cancer; HER2 positive (HER2+) breast cancer; HER2negative (HER2−) breast cancer; Estrogen Receptor negative (ER−) breastcancer; Estrogen Receptor positive (ER+) breast cancer; ProgesteroneReceptor negative (PR−) breast cancer; Progesterone Receptor positive(PR+) breast cancer; ER positive (ER+) and PR positive (PR+) breastcancer; ER positive (ER+) and PR negative (PR−) breast cancer; ERnegative (ER−) and PR positive (PR+) breast cancer; ER positive (ER+)and HER2 negative (HER2−) breast cancer; ER−, PR−, and HER2− triplenegative breast cancer (ER−, PR−, HER2−; TNBC); hormone receptornegative breast cancer (ER− and PR−); ER+, PR+, and HER2+ triplepositive breast cancer (ER+, PR+, HER2+; TPBC); hepatocellular carcinoma(HCC); head and neck squamous cell carcinoma (HNSCC); oral tonguesquamous cell carcinoma (OTSCC); sarcomas (e.g. epitheloid, rhabdoid andsynovial); esophageal cancer; gastric cancer; ovarian cancer; pancreaticcancer; lung cancer; non-small cell lung carcinoma (NSCLC); small-celllung carcinoma (SCLC); squamous cell carcinoma (SCC); head and neckcancer; head and neck squamous cell carcinoma (HNSCC); gastrointestinalcancer; large intestinal cancer; small intestinal cancer; stomachcancer; colon cancer; colorectal cancer; bladder cancer; liver cancer;biliary tract cancer; urothelial cancer; endometrial cancer; cervicalcancer; prostate cancer; mesothelioma; chordoma; renal cancer; renalcell carcinoma (RCC); brain cancer; neuroblastoma; glioblastoma; skincancer; melanoma; basal cell carcinoma; merkel cell carcinoma; bloodcancer; hematopoetic cancer; myeloma; multiple myeloma (MM); B cellmalignancies; lymphoma; B cell lymphoma; Hodgkin lymphoma; T celllymphoma; leukemia; or acute lymphocytic leukemia (ALL). In certainembodiments, the compound comprises an antisense compound targeted toMALAT1. In certain embodiments, the compound comprises anoligonucleotide targeted to MALAT1. In certain embodiments, the compoundcomprises a modified oligonucleotide consisting of 8 to 80 linkednucleosides and having a nucleobase sequence comprising at least 8contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs:2-10. In certain embodiments, the compound comprises a modifiedoligonucleotide consisting of 16 to 80 linked nucleosides and having anucleobase sequence comprising the nucleobase sequence of any one of SEQID NOs: 2-10. In certain embodiments, the compound comprises a modifiedoligonucleotide consisting of the nucleobase sequence of any one of SEQID NOs: 2-10. In certain embodiments, a compound comprises a modifiedoligonucleotide consisting of 8 to 80 linked nucleosides and having anucleobase sequence comprising at least 8 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 36-2646 or 2664-2813. Incertain embodiments, a compound comprises a modified oligonucleotideconsisting of 16 to 80 linked nucleosides and having a nucleobasesequence comprising the nucleobase sequence of any one of SEQ ID NOs:36-2646 or 2664-2813. In certain embodiments, a compound comprises amodified oligonucleotide consisting of the nucleobase sequence of anyone of SEQ ID NOs: SEQ ID NOs: 36-2646 or 2664-2813. In any of theforegoing embodiments, the modified oligonucleotide can consist of 10 to30 linked nucleosides. In certain embodiments, the compound is ION1157034, 1157111, 1157190, 1157929, 1158161, 1158162, 1304884, 1304890,or 1304906. In any of the foregoing embodiments, the compound can besingle-stranded or double-stranded. In any of the foregoing embodiments,the compound can be an antisense compound or oligomeric compound.

In certain embodiments, a method of reducing or inhibiting cancer cellproliferation, cancer cell migration, cancer cell branchingmorphogenesis, tumor progression, tumor growth, or metastasis of anindividual having, or at risk of having, a cancer associated with MALAT1comprises administering to the individual a compound comprising a MALAT1specific inhibitor, thereby reducing or inhibiting cancer cellproliferation, cancer cell migration, cancer cell branchingmorphogenesis, tumor progression, tumor growth, or metastasis in theindividual. In certain embodiments, a method of increasing or inducingcancer cell differentiation, cancer cell adhesion, or tumordifferentiation of an individual having, or at risk of having, a cancerassociated with MALAT1 comprises administering to the individual acompound comprising a MALAT1 specific inhibitor, thereby increasing orinducing cancer cell differentiation, cancer cell adhesion, or tumordifferentiation in the individual. In certain embodiments, administeringthe compound induces a breast cancer cell or breast tumor to have acystic, ductular, or acinar phenotype or morphology. In certainembodiments, administering the compound induces a breast cancer cell orbreast tumor to have a more differentiated phenotype or structure. Incertain embodiments, the more differentiated phenotype or structureincludes, but is not limited to, presence of secretory lipid droplets,increased desmosomal structures, polarized ductal structures, orincreased levels of differentiation markers such as E-cadherin or milkproteins such as casein. In certain embodiments, the individual has, oris at risk of having, breast cancer; inflammatory breast cancer; breastductal carcinoma; breast lobular carcinoma; luminal A breast cancer;luminal B breast cancer; basal-like breast cancer; HER2 positive (HER2+)breast cancer; HER2 negative (HER2−) breast cancer; Estrogen Receptornegative (ER−) breast cancer; Estrogen Receptor positive (ER+) breastcancer; Progesterone Receptor negative (PR−) breast cancer; ProgesteroneReceptor positive (PR+) breast cancer; ER positive (ER+) and PR positive(PR+) breast cancer; ER positive (ER+) and PR negative (PR−) breastcancer; ER negative (ER−) and PR positive (PR+) breast cancer; ERpositive (ER+) and HER2 negative (HER2−) breast cancer; ER−, PR−, andHER2− triple negative breast cancer (ER−, PR−, HER2−; TNBC); hormonereceptor negative breast cancer (ER− and PR−); ER+, PR+, and HER2+triple positive breast cancer (ER+, PR+, HER2+; TPBC); hepatocellularcarcinoma (HCC); head and neck squamous cell carcinoma (HNSCC); oraltongue squamous cell carcinoma (OTSCC); sarcomas (e.g. epitheloid,rhabdoid and synovial); esophageal cancer; gastric cancer; ovariancancer; pancreatic cancer; lung cancer; non-small cell lung carcinoma(NSCLC); small-cell lung carcinoma (SCLC); squamous cell carcinoma(SCC); head and neck cancer; head and neck squamous cell carcinoma(HNSCC); gastrointestinal cancer; large intestinal cancer; smallintestinal cancer; stomach cancer; colon cancer; colorectal cancer;bladder cancer; liver cancer; biliary tract cancer; urothelial cancer;endometrial cancer; cervical cancer; prostate cancer; mesothelioma;chordoma; renal cancer; renal cell carcinoma (RCC); brain cancer;neuroblastoma; glioblastoma; skin cancer; melanoma; basal cellcarcinoma; merkel cell carcinoma; blood cancer; hematopoetic cancer;myeloma; multiple myeloma (MM); B cell malignancies; lymphoma; B celllymphoma; Hodgkin lymphoma; T cell lymphoma; leukemia; or acutelymphocytic leukemia (ALL). In certain embodiments, the compoundcomprises an antisense compound targeted to MALAT1. In certainembodiments, the compound comprises an oligonucleotide targeted toMALAT1. In certain embodiments, the compound comprises a modifiedoligonucleotide consisting of 8 to 80 linked nucleosides and having anucleobase sequence comprising at least 8 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 2-10. In certain embodiments,the compound comprises a modified oligonucleotide consisting of 16 to 80linked nucleosides and having a nucleobase sequence comprising thenucleobase sequence of any one of SEQ ID NOs: 2-10. In certainembodiments, the compound comprises a modified oligonucleotideconsisting of the nucleobase sequence of any one of SEQ ID NOs: 2-10. Incertain embodiments, a compound comprises a modified oligonucleotideconsisting of 8 to 80 linked nucleosides and having a nucleobasesequence comprising at least 8 contiguous nucleobases of any of thenucleobase sequences of SEQ ID NOs: 36-2646 or 2664-2813. In certainembodiments, a compound comprises a modified oligonucleotide consistingof 16 to 80 linked nucleosides and having a nucleobase sequencecomprising the nucleobase sequence of any one of SEQ ID NOs: 36-2646 or2664-2813. In certain embodiments, a compound comprises a modifiedoligonucleotide consisting of the nucleobase sequence of any one of SEQID NOs: SEQ ID NOs: 36-2646 or 2664-2813. In any of the foregoingembodiments, the modified oligonucleotide can consist of 10 to 30 linkednucleosides. In certain embodiments, the compound is ION 1157034,1157111, 1157190, 1157929, 1158161, 1158162, 1304884, 1304890, or1304906. In any of the foregoing embodiments, the compound can besingle-stranded or double-stranded. In any of the foregoing embodiments,the compound can be an antisense compound or oligomeric compound. Incertain embodiments, the compound is administered to the individualparenterally. In certain embodiments, the individual is identified ashaving or at risk of having a cancer associated with MALAT1.

Certain embodiments are drawn to a compound comprising a MALAT1 specificinhibitor for use in treating cancer. In certain embodiments, the canceris breast cancer; inflammatory breast cancer; breast ductal carcinoma;breast lobular carcinoma; luminal A breast cancer; luminal B breastcancer; basal-like breast cancer; HER2 positive (HER2+) breast cancer;HER2 negative (HER2−) breast cancer; Estrogen Receptor negative (ER−)breast cancer; Estrogen Receptor positive (ER+) breast cancer;Progesterone Receptor negative (PR−) breast cancer; ProgesteroneReceptor positive (PR+) breast cancer; ER positive (ER+) and PR positive(PR+) breast cancer; ER positive (ER+) and PR negative (PR−) breastcancer; ER negative (ER−) and PR positive (PR+) breast cancer; ERpositive (ER+) and HER2 negative (HER2−) breast cancer; ER−, PR−, andHER2− triple negative breast cancer (ER−, PR−, HER2−; TNBC); hormonereceptor negative breast cancer (ER− and PR−); ER+, PR+, and HER2+triple positive breast cancer (ER+, PR+, HER2+; TPBC); hepatocellularcarcinoma (HCC); head and neck squamous cell carcinoma (HNSCC); oraltongue squamous cell carcinoma (OTSCC); sarcomas (e.g. epitheloid,rhabdoid and synovial); esophageal cancer; gastric cancer; ovariancancer; pancreatic cancer; lung cancer; non-small cell lung carcinoma(NSCLC); small-cell lung carcinoma (SCLC); squamous cell carcinoma(SCC); head and neck cancer; head and neck squamous cell carcinoma(HNSCC); gastrointestinal cancer; large intestinal cancer; smallintestinal cancer; stomach cancer; colon cancer; colorectal cancer;bladder cancer; liver cancer; biliary tract cancer; urothelial cancer;endometrial cancer; cervical cancer; prostate cancer; mesothelioma;chordoma; renal cancer; renal cell carcinoma (RCC); brain cancer;neuroblastoma; glioblastoma; skin cancer; melanoma; basal cellcarcinoma; merkel cell carcinoma; blood cancer; hematopoetic cancer;myeloma; multiple myeloma (MM); B cell malignancies; lymphoma; B celllymphoma; Hodgkin lymphoma; T cell lymphoma; leukemia; or acutelymphocytic leukemia (ALL). In certain embodiments, the compoundcomprises an antisense compound targeted to MALAT1. In certainembodiments, the compound comprises an oligonucleotide targeted toMALAT1. In certain embodiments, the compound comprises a modifiedoligonucleotide consisting of 8 to 80 linked nucleosides and having anucleobase sequence comprising at least 8 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 2-10. In certain embodiments,the compound comprises a modified oligonucleotide consisting of 16 to 80linked nucleosides and having a nucleobase sequence comprising thenucleobase sequence of any one of SEQ ID NOs: 2-10. In certainembodiments, the compound comprises a modified oligonucleotideconsisting of the nucleobase sequence of any one of SEQ ID NOs: 2-10. Incertain embodiments, a compound comprises a modified oligonucleotideconsisting of 8 to 80 linked nucleosides and having a nucleobasesequence comprising at least 8 contiguous nucleobases of any of thenucleobase sequences of SEQ ID NOs: 36-2646 or 2664-2813. In certainembodiments, a compound comprises a modified oligonucleotide consistingof 16 to 80 linked nucleosides and having a nucleobase sequencecomprising the nucleobase sequence of any one of SEQ ID NOs: 36-2646 or2664-2813. In certain embodiments, a compound comprises a modifiedoligonucleotide consisting of the nucleobase sequence of any one of SEQID NOs: SEQ ID NOs: 36-2646 or 2664-2813. In any of the foregoingembodiments, the modified oligonucleotide can consist of 10 to 30 linkednucleosides. In certain embodiments, the compound is ION 1157034,1157111, 1157190, 1157929, 1158161, 1158162, 1304884, 1304890, or1304906. In any of the foregoing embodiments, the compound can besingle-stranded or double-stranded. In any of the foregoing embodiments,the compound can be an antisense compound or oligomeric compound.

Certain embodiments are drawn to a compound comprising a MALAT1 specificinhibitor for use in reducing or inhibiting cancer cell proliferation,cancer cell migration, cancer cell branching morphogenesis, tumorprogression, tumor growth, or metastasis in an individual having cancer.Certain embodiments are drawn to a compound comprising a MALAT1 specificinhibitor for use in increasing or inducing cancer cell differentiation,cancer cell adhesion, or tumor differentiation in an individual havingcancer. In certain embodiments, administering the compound induces abreast cancer cell or breast tumor to have a cystic, ductular, or acinarphenotype or morphology. In certain embodiments, administering thecompound induces a breast cancer cell or breast tumor to have a moredifferentiated phenotype or structure. In certain embodiments, the moredifferentiated phenotype or structure includes, but is not limited to,presence of secretory lipid droplets, increased desmosomal structures,polarized ductal structures, or increased levels of differentiationmarkers such as E-cadherin or milk proteins such as casein. In certainembodiments, the cancer is breast cancer; inflammatory breast cancer;breast ductal carcinoma; breast lobular carcinoma; luminal A breastcancer; luminal B breast cancer; basal-like breast cancer; HER2 positive(HER2+) breast cancer; HER2 negative (HER2−) breast cancer; EstrogenReceptor negative (ER−) breast cancer; Estrogen Receptor positive (ER+)breast cancer; Progesterone Receptor negative (PR−) breast cancer;Progesterone Receptor positive (PR+) breast cancer; ER positive (ER+)and PR positive (PR+) breast cancer; ER positive (ER+) and PR negative(PR−) breast cancer; ER negative (ER−) and PR positive (PR+) breastcancer; ER positive (ER+) and HER2 negative (HER2−) breast cancer; ER−,PR−, and HER2− triple negative breast cancer (ER−, PR−, HER2−; TNBC);hormone receptor negative breast cancer (ER− and PR−); ER+, PR+, andHER2+ triple positive breast cancer (ER+, PR+, HER2+; TPBC);hepatocellular carcinoma (HCC); head and neck squamous cell carcinoma(HNSCC); oral tongue squamous cell carcinoma (OTSCC); sarcomas (e.g.epitheloid, rhabdoid and synovial); esophageal cancer; gastric cancer;ovarian cancer; pancreatic cancer; lung cancer; non-small cell lungcarcinoma (NSCLC); small-cell lung carcinoma (SCLC); squamous cellcarcinoma (SCC); head and neck cancer; head and neck squamous cellcarcinoma (HNSCC); gastrointestinal cancer; large intestinal cancer;small intestinal cancer; stomach cancer; colon cancer; colorectalcancer; bladder cancer; liver cancer; biliary tract cancer; urothelialcancer; endometrial cancer; cervical cancer; prostate cancer;mesothelioma; chordoma; renal cancer; renal cell carcinoma (RCC); braincancer; neuroblastoma; glioblastoma; skin cancer; melanoma; basal cellcarcinoma; merkel cell carcinoma; blood cancer; hematopoetic cancer;myeloma; multiple myeloma (MM); B cell malignancies; lymphoma; B celllymphoma; Hodgkin lymphoma; T cell lymphoma; leukemia; or acutelymphocytic leukemia (ALL). In certain embodiments, the compoundcomprises an antisense compound targeted to MALAT1. In certainembodiments, the compound comprises an oligonucleotide targeted toMALAT1. In certain embodiments, the compound comprises a modifiedoligonucleotide consisting of 8 to 80 linked nucleosides and having anucleobase sequence comprising at least 8 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 2-10. In certain embodiments,the compound comprises a modified oligonucleotide consisting of 16 to 80linked nucleosides and having a nucleobase sequence comprising thenucleobase sequence of any one of SEQ ID NOs: 2-10. In certainembodiments, the compound comprises a modified oligonucleotideconsisting of the nucleobase sequence of any one of SEQ ID NOs: 2-10. Incertain embodiments, a compound comprises a modified oligonucleotideconsisting of 8 to 80 linked nucleosides and having a nucleobasesequence comprising at least 8 contiguous nucleobases of any of thenucleobase sequences of SEQ ID NOs: 36-2646 or 2664-2813. In certainembodiments, a compound comprises a modified oligonucleotide consistingof 16 to 80 linked nucleosides and having a nucleobase sequencecomprising the nucleobase sequence of any one of SEQ ID NOs: 36-2646 or2664-2813. In certain embodiments, a compound comprises a modifiedoligonucleotide consisting of the nucleobase sequence of any one of SEQID NOs: SEQ ID NOs: 36-2646 or 2664-2813. In any of the foregoingembodiments, the modified oligonucleotide can consist of 10 to 30 linkednucleosides. In certain embodiments, the compound is ION 1157034,1157111, 1157190, 1157929, 1158161, 1158162, 1304884, 1304890, or1304906. In any of the foregoing embodiments, the compound can besingle-stranded or double-stranded. In any of the foregoing embodiments,the compound can be an antisense compound or oligomeric compound.

Certain embodiments are drawn to use of a compound comprising a MALAT1specific inhibitor for the manufacture or preparation of a medicamentfor treating cancer. Certain embodiments are drawn to use of a compoundcomprising a MALAT1 specific inhibitor for the preparation of amedicament for treating a cancer associated with MALAT1. In certainembodiments, the cancer is breast cancer; inflammatory breast cancer;breast ductal carcinoma; breast lobular carcinoma; luminal A breastcancer; luminal B breast cancer; basal-like breast cancer; HER2 positive(HER2+) breast cancer; HER2 negative (HER2−) breast cancer; EstrogenReceptor negative (ER−) breast cancer; Estrogen Receptor positive (ER+)breast cancer; Progesterone Receptor negative (PR−) breast cancer;Progesterone Receptor positive (PR+) breast cancer; ER positive (ER+)and PR positive (PR+) breast cancer; ER positive (ER+) and PR negative(PR−) breast cancer; ER negative (ER−) and PR positive (PR+) breastcancer; ER positive (ER+) and HER2 negative (HER2−) breast cancer; ER−,PR−, and HER2− triple negative breast cancer (ER−, PR−, HER2−; TNBC);hormone receptor negative breast cancer (ER− and PR−); ER+, PR+, andHER2+ triple positive breast cancer (ER+, PR+, HER2+; TPBC);hepatocellular carcinoma (HCC); head and neck squamous cell carcinoma(HNSCC); oral tongue squamous cell carcinoma (OTSCC); sarcomas (e.g.epitheloid, rhabdoid and synovial); esophageal cancer; gastric cancer;ovarian cancer; pancreatic cancer; lung cancer; non-small cell lungcarcinoma (NSCLC); small-cell lung carcinoma (SCLC); squamous cellcarcinoma (SCC); head and neck cancer; head and neck squamous cellcarcinoma (HNSCC); gastrointestinal cancer; large intestinal cancer;small intestinal cancer; stomach cancer; colon cancer; colorectalcancer; bladder cancer; liver cancer; biliary tract cancer; urothelialcancer; endometrial cancer; cervical cancer; prostate cancer;mesothelioma; chordoma; renal cancer; renal cell carcinoma (RCC); braincancer; neuroblastoma; glioblastoma; skin cancer; melanoma; basal cellcarcinoma; merkel cell carcinoma; blood cancer; hematopoetic cancer;myeloma; multiple myeloma (MM); B cell malignancies; lymphoma; B celllymphoma; Hodgkin lymphoma; T cell lymphoma; leukemia; or acutelymphocytic leukemia (ALL). In certain embodiments, the compoundcomprises an antisense compound targeted to MALAT1. In certainembodiments, the compound comprises an oligonucleotide targeted toMALAT1. In certain embodiments, the compound comprises a modifiedoligonucleotide consisting of 8 to 80 linked nucleosides and having anucleobase sequence comprising at least 8 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 2-10. In certain embodiments,the compound comprises a modified oligonucleotide consisting of 16 to 80linked nucleosides and having a nucleobase sequence comprising thenucleobase sequence of any one of SEQ ID NOs: 2-10. In certainembodiments, the compound comprises a modified oligonucleotideconsisting of the nucleobase sequence of any one of SEQ ID NOs: 2-10. Incertain embodiments, a compound comprises a modified oligonucleotideconsisting of 8 to 80 linked nucleosides and having a nucleobasesequence comprising at least 8 contiguous nucleobases of any of thenucleobase sequences of SEQ ID NOs: 36-2646 or 2664-2813. In certainembodiments, a compound comprises a modified oligonucleotide consistingof 16 to 80 linked nucleosides and having a nucleobase sequencecomprising the nucleobase sequence of any one of SEQ ID NOs: 36-2646 or2664-2813. In certain embodiments, a compound comprises a modifiedoligonucleotide consisting of the nucleobase sequence of any one of SEQID NOs: SEQ ID NOs: 36-2646 or 2664-2813. In any of the foregoingembodiments, the modified oligonucleotide can consist of 10 to 30 linkednucleosides. In certain embodiments, the compound is ION 1157034,1157111, 1157190, 1157929, 1158161, 1158162, 1304884, 1304890, or1304906. In any of the foregoing embodiments, the compound can besingle-stranded or double-stranded. In any of the foregoing embodiments,the compound can be an antisense compound or oligomeric compound.

Certain embodiments are drawn to use of a compound comprising a MALAT1specific inhibitor for the manufacture or preparation of a medicamentfor reducing or inhibiting cancer cell proliferation, cancer cellmigration, cancer cell branching morphogenesis, tumor progression, tumorgrowth, or metastasis in an individual having cancer. Certainembodiments are drawn to use of a compound comprising a MALAT1 specificinhibitor for the manufacture or preparation of a medicament forincreasing or inducing cancer cell differentiation, cancer celladhesion, or tumor differentiation in an individual having cancer. Incertain embodiments, administering the compound induces a breast cancercell or breast tumor to have a cystic, ductular, or acinar phenotype ormorphology. In certain embodiments, administering the compound induces abreast cancer cell or breast tumor to have a more differentiatedphenotype or structure. In certain embodiments, the more differentiatedphenotype or structure includes, but is not limited to, presence ofsecretory lipid droplets, increased desmosomal structures, polarizedductal structures, or increased levels of differentiation markers suchas E-cadherin or milk proteins such as casein. In certain embodiments,the cancer is breast cancer; inflammatory breast cancer; breast ductalcarcinoma; breast lobular carcinoma; luminal A breast cancer; luminal Bbreast cancer; basal-like breast cancer; HER2 positive (HER2+) breastcancer; HER2 negative (HER2−) breast cancer; Estrogen Receptor negative(ER−) breast cancer; Estrogen Receptor positive (ER+) breast cancer;Progesterone Receptor negative (PR−) breast cancer; ProgesteroneReceptor positive (PR+) breast cancer; ER positive (ER+) and PR positive(PR+) breast cancer; ER positive (ER+) and PR negative (PR−) breastcancer; ER negative (ER−) and PR positive (PR+) breast cancer; ERpositive (ER+) and HER2 negative (HER2−) breast cancer; ER−, PR−, andHER2− triple negative breast cancer (ER−, PR−, HER2−; TNBC); hormonereceptor negative breast cancer (ER− and PR−); ER+, PR+, and HER2+triple positive breast cancer (ER+, PR+, HER2+; TPBC); hepatocellularcarcinoma (HCC); head and neck squamous cell carcinoma (HNSCC); oraltongue squamous cell carcinoma (OTSCC); sarcomas (e.g. epitheloid,rhabdoid and synovial); esophageal cancer; gastric cancer; ovariancancer; pancreatic cancer; lung cancer; non-small cell lung carcinoma(NSCLC); small-cell lung carcinoma (SCLC); squamous cell carcinoma(SCC); head and neck cancer; head and neck squamous cell carcinoma(HNSCC); gastrointestinal cancer; large intestinal cancer; smallintestinal cancer; stomach cancer; colon cancer; colorectal cancer;bladder cancer; liver cancer; biliary tract cancer; urothelial cancer;endometrial cancer; cervical cancer; prostate cancer; mesothelioma;chordoma; renal cancer; renal cell carcinoma (RCC); brain cancer;neuroblastoma; glioblastoma; skin cancer; melanoma; basal cellcarcinoma; merkel cell carcinoma; blood cancer; hematopoetic cancer;myeloma; multiple myeloma (MM); B cell malignancies; lymphoma; B celllymphoma; Hodgkin lymphoma; T cell lymphoma; leukemia; or acutelymphocytic leukemia (ALL). In certain embodiments, the compoundcomprises an antisense compound targeted to MALAT1. In certainembodiments, the compound comprises an oligonucleotide targeted toMALAT1. In certain embodiments, the compound comprises a modifiedoligonucleotide consisting of 8 to 80 linked nucleosides and having anucleobase sequence comprising at least 8 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 2-10. In certain embodiments,the compound comprises a modified oligonucleotide consisting of 16 to 80linked nucleosides and having a nucleobase sequence comprising thenucleobase sequence of any one of SEQ ID NOs: 2-10. In certainembodiments, the compound comprises a modified oligonucleotideconsisting of the nucleobase sequence of any one of SEQ ID NOs: 2-10. Incertain embodiments, a compound comprises a modified oligonucleotideconsisting of 8 to 80 linked nucleosides and having a nucleobasesequence comprising at least 8 contiguous nucleobases of any of thenucleobase sequences of SEQ ID NOs: 36-2646 or 2664-2813. In certainembodiments, a compound comprises a modified oligonucleotide consistingof 16 to 80 linked nucleosides and having a nucleobase sequencecomprising the nucleobase sequence of any one of SEQ ID NOs: 36-2646 or2664-2813. In certain embodiments, a compound comprises a modifiedoligonucleotide consisting of the nucleobase sequence of any one of SEQID NOs: SEQ ID NOs: 36-2646 or 2664-2813. In any of the foregoingembodiments, the modified oligonucleotide can consist of 10 to 30 linkednucleosides. In certain embodiments, the compound is ION 1157034,1157111, 1157190, 1157929, 1158161, 1158162, 1304884, 1304890, or1304906. In any of the foregoing embodiments, the compound can besingle-stranded or double-stranded. In any of the foregoing embodiments,the compound can be an antisense compound or oligomeric compound.

In any of the foregoing methods or uses, the compound can be targeted toMALAT1. In certain embodiments, the compound comprises or consists of amodified oligonucleotide, for example a modified oligonucleotide canconsist of 8 to 80 linked nucleosides, 10 to 30 linked nucleosides, 12to 30 linked nucleosides, or 20 linked nucleosides. In certainembodiments, the modified oligonucleotide is at least 80%, 85%, 90%, 95%or 100% complementary to SEQ ID NO: 1. In certain embodiments, themodified oligonucleotide comprises at least one modified internucleosidelinkage, at least one modified sugar and/or at least one modifiednucleobase. In certain embodiments, the modified internucleoside linkageis a phosphorothioate internucleoside linkage, the modified sugar is abicyclic sugar or a 2′-O-methoxyethyl, and the modified nucleobase is a5-methylcytosine. In certain embodiments, the modified oligonucleotidecomprises a gap segment consisting of linked 2′-deoxynucleosides; a 5′wing segment consisting of linked nucleosides; and a 3′ wing segmentconsisting of linked nucleosides, wherein the gap segment is positionedimmediately adjacent to and between the 5′ wing segment and the 3′ wingsegment and wherein each nucleoside of each wing segment comprises amodified sugar.

In any of the foregoing embodiments, the modified oligonucleotide canconsist of 12 to 30, 15 to 30, 15 to 25, 15 to 24, 16 to 24, 17 to 24,18 to 24, 19 to 24, 20 to 24, 19 to 22, 20 to 22, 16 to 20, or 17 or 20linked nucleosides. In certain embodiments, the modified oligonucleotideis at least 80%, 85%, 90%, 95% or 100% complementary to SEQ ID NO: 1. Incertain embodiments, at least one internucleoside linkage of themodified oligonucleotide is a modified internucleoside linkage, at leastone sugar of the modified oligonucleotide is a modified sugar and/or atleast one nucleobase of the modified oligonucleotide is a modifiednucleobase. In certain embodiments, the modified internucleoside linkageis a phosphorothioate internucleoside linkage, the modified sugar is abicyclic sugar or a 2′-O-methoxyethyl sugar, and the modified nucleobaseis 5-methylcytosine. In certain embodiments, the modifiedoligonucleotide has a gap segment consisting of linked2′-deoxynucleosides; a 5′ wing segment consisting of linked nucleosides;and a 3′ wing segment consisting of linked nucleosides, wherein the gapsegment is positioned immediately adjacent to and between the 5′ wingsegment and the 3′ wing segment and wherein each nucleoside of each wingsegment comprises a modified sugar.

In any of the foregoing methods or uses, the compound can comprise orconsist of a modified oligonucleotide having:

-   -   a gap segment consisting of linked 2′-deoxynucleosides;    -   a 5′ wing segment consisting of linked nucleosides; and    -   a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment and wherein each nucleoside of each wing segmentcomprises a modified sugar. In certain embodiments, the modifiedoligonucleotide consists of 16 to 80 linked nucleosides and has anucleobase sequence comprising the nucleobase sequence recited in anyone of SEQ ID NOs: 2-10 or 36-2813. In certain embodiments, the modifiedoligonucleotide consists of 16 to 80 linked nucleosides and has anucleobase sequence comprising the nucleobase sequence recited in anyone of SEQ ID NOs: 2-10. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides and has anucleobase sequence comprising the nucleobase sequence recited in anyone of SEQ ID NOs: 2-10 or 36-2813. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides and has anucleobase sequence comprising the nucleobase sequence recited in anyone of SEQ ID NOs: 2-10. In certain embodiments, the modifiedoligonucleotide consists of 16 linked nucleosides and has a nucleobasesequence consisting of the nucleobase sequence recited in any one of SEQID NOs: 2-10 or 36-2813. In certain embodiments, the modifiedoligonucleotide consists of 16 linked nucleosides and has a nucleobasesequence consisting of the nucleobase sequence recited in any one of SEQID NOs: 2-10.

In any of the foregoing methods or uses, the compound can comprise orconsist of a modified oligonucleotide consisting of 16 to 80 linkednucleobases and having a nucleobase sequence comprising the nucleobasesequence recited in any one of SEQ ID NOs: 2-10 or 36-2813, wherein themodified oligonucleotide has:

-   -   a gap segment consisting of linked 2′-deoxynucleosides;    -   a 5′ wing segment consisting of linked nucleosides; and    -   a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment and wherein each nucleoside of each wing segmentcomprises a modified sugar. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 linkednucleosides.

In any of the foregoing methods or uses, the compound can comprise orconsist of a modified oligonucleotide consisting of 16 to 80 linkednucleobases and having a nucleobase sequence comprising the nucleobasesequence recited in any one of SEQ ID NOs: 2-10, wherein the modifiedoligonucleotide has:

-   -   a gap segment consisting of linked 2′-deoxynucleosides;    -   a 5′ wing segment consisting of linked nucleosides; and    -   a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment and wherein each nucleoside of each wing segmentcomprises a modified sugar. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 linkednucleosides.

In any of the foregoing methods or uses, the compound can comprise orconsist of a modified oligonucleotide consisting of 16 to 80 linkednucleobases and having a nucleobase sequence comprising the nucleobasesequence recited in any one of SEQ ID NOs: 36-2646 or 2664-2813, whereinthe modified oligonucleotide has:

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment; wherein each nucleoside of each wing segmentcomprises a cEt nucleoside; wherein each internucleoside linkage is aphosphorothioate linkage; and wherein each cytosine is 5-methylcytosine.In certain embodiments, the modified oligonucleotide consists of 16 to30 linked nucleosides. In certain embodiments, the modifiedoligonucleotide consists of 16 linked nucleosides.

In any of the foregoing methods or uses, the compound can comprise orconsist of a modified oligonucleotide consisting of 16 to 80 linkednucleobases and having a nucleobase sequence comprising the nucleobasesequence recited in any one of SEQ ID NOs: 2-7, wherein the modifiedoligonucleotide has:

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment; wherein each nucleoside of each wing segmentcomprises a cEt nucleoside; wherein each internucleoside linkage is aphosphorothioate linkage; and wherein each cytosine is 5-methylcytosine.In certain embodiments, the modified oligonucleotide consists of 16 to30 linked nucleosides. In certain embodiments, the modifiedoligonucleotide consists of 16 linked nucleosides.

In any of the foregoing methods or uses, the compound can comprise orconsist of a modified oligonucleotide having a nucleobase sequencecomprising the nucleobase sequence recited in any of SEQ ID NOs: 8-10;wherein the modified oligonucleotide comprises the sugar motifkkk-d-y-d(8)-kkk, wherein “k” indicates a cEt modified sugar moiety, “d”indicates an unmodified 2′-deoxyribosyl sugar moiety, and “y” indicatesa 2′-O-methyl modified sugar moiety; wherein each internucleosidelinkage is a phosphorothioate linkage; and wherein each cytosine is5-methylcytosine. In certain embodiments, the modified oligonucleotideconsisting of 16 to 30 linked nucleosides. In certain embodiments, themodified oligonucleotide consists of 16 linked nucleosides.

In any of the foregoing methods or uses, the compound can comprise orconsist of ION 1304884 having the nucleobase sequence and chemicalmotif: GksGksAksTdsUysAdsAdsTdsGdsTdsAdsGdsTdsGksTksAk (SEQ ID NO: 8),wherein “d” represents a 2′-deoxyribose sugar, “k” represents a cEtmodified sugar, “y” represents a 2′-O-methyl modified sugar, “s”represents a phosphorothioate internucleoside linkage, and “mC” refersto 5-methylcytosine. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 linkednucleosides.

In any of the foregoing methods or uses, the compound can comprise orconsist of ION 1304890 having the nucleobase sequence and chemicalmotif: GksGksTksTdsAysTdsAdsGdsmCdsTdsTdsGdsAdsmCksAksAk (SEQ ID NO: 9),wherein “d” represents a 2′-deoxyribose sugar, “k” represents a cEtmodified sugar, “y” represents a 2′-O-methyl modified sugar, “s”represents a phosphorothioate internucleoside linkage, and “mC” refersto a 5-methylcytosine. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 linkednucleosides.

In any of the foregoing methods or uses, the compound can comprise orconsist of ION 1304906 having the nucleobase sequence and chemicalmotif: GksmCksAksGdsAysTdsAdsAdsTdsGdsTdsTdsmCdsTksmCksAk (SEQ ID NO:10), wherein “d” represents a 2′-deoxyribose sugar, “k” represents a cEtmodified sugar, “y” represents a 2′-O-methyl modified sugar, “s”represents a phosphorothioate internucleoside linkage, and “mC” refersto 5-methylcytosine. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 linkednucleosides.

In any of the foregoing methods or uses, the compound can be a modifiedoligonucleotide according to the following chemical structure:

or a salt thereof. In certain embodiments, the modified oligonucleotideis the sodium salt or potassium salt.

In any of the foregoing methods or uses, the compound can be a modifiedoligonucleotide according to the following chemical structure:

In any of the foregoing methods or uses, the compound can beadministered parenterally. For example, in certain embodiments thecompound can be administered through injection or infusion. Parenteraladministration includes subcutaneous administration, intravenousadministration, intramuscular administration, intraarterialadministration, intraperitoneal administration, or intracranialadministration, e.g. intrathecal or intracerebroventricularadministration.

Certain Combinations and Combination Therapies

In certain embodiments, a first agent comprising a compound describedherein is co-administered with one or more secondary agents. In certainembodiments, such second agents are designed to treat the same disease,disorder, or condition as the first agent described herein. In certainembodiments, such second agents are designed to treat a differentdisease, disorder, or condition as the first agent described herein. Incertain embodiments, a first agent is designed to treat an undesiredside effect of a second agent. In certain embodiments, second agents areco-administered with the first agent to treat an undesired effect of thefirst agent. In certain embodiments, such second agents are designed totreat an undesired side effect of one or more pharmaceuticalcompositions as described herein. In certain embodiments, second agentsare co-administered with the first agent to produce a combinationaleffect. In certain embodiments, second agents are co-administered withthe first agent to produce a synergistic effect. In certain embodiments,the co-administration of the first and second agents permits use oflower dosages than would be required to achieve a therapeutic orprophylactic effect if the agents were administered as independenttherapy.

In certain embodiments, one or more compounds or compositions providedherein are co-administered with one or more secondary agents. In certainembodiments, one or more compounds or compositions provided herein andone or more secondary agents, are administered at different times. Incertain embodiments, one or more compounds or compositions providedherein and one or more secondary agents, are prepared together in asingle formulation. In certain embodiments, one or more compounds orcompositions provided herein and one or more secondary agents, areprepared separately. In certain embodiments, a secondary agent isselected from: a chemotherapeutic agent including, but not limited to,capecitabine (Xeloda), carboplatin, cisplatin, cyclophosphamide,docetaxel (Taxotere), doxorubicin, epirubicin (Ellence), eribulin(Halaven), fluorouracil (5-FU, Efudex), gemcitabine (Gemzar),ixabepilone (Ixempra), methotrexate (Rheumatrex, Trexall), paclitaxel(Taxol), or vinorelbine (Navelbine); a combination regiment including,but not limited to, AC (doxorubicin and cyclophosphamide), EC(epirubicin, cyclophosphamide), AC or EC (epirubicin andcyclophosphamide) followed by T (doxorubicin and cyclophosphamide,followed by paclitaxel or docetaxel), CAF (cyclophosphamide,doxorubicin, and 5-FU), CEF (cyclophosphamide, epirubicin, and 5-FU),CMF (cyclophosphamide, methotrexate, and 5-FU), TAC (docetaxel,doxorubicin, and cyclophosphamide), TC (docetaxel and cyclophosphamide),AC-TH (doxorubicin, cyclophosphamide, paclitaxel, trastuzumab), AC-THP(doxorubicin, cyclophosphamide, paclitaxel, trastuzumab, pertuzumab),TCHP (docetaxel, carboplatin, trastuzumab, pertuzumab), TCH (docetaxel,carboplatin, trastuzumab), or TH (paclitaxel, trastuzumab); hormonetherapy including, but not limited to, selective estrogen receptormodulators, tamoxifen, toremifene (Fareston), fulvestrant (Faslodex),goserelin (Zoladex), or leuprolide (Eligard, Lupron); aromataseinhibitors (AIs) including, but not limited to, anastrozole (Arimidex),exemestane (Aromasin), or letrozole (Femara); HER2-targeted therapyincluding, but not limited to, trastuzumab (Herceptin), lapatinib(TYKERB), pertuzumab (Perjeta), or neratinib (Nerlynx).

Certain embodiments are directed to the use of a compound targeted toMALAT1 as described herein in combination with a secondary agent. Inparticular embodiments such use is in a method of treating a patientsuffering from cancer including, but not limited to, breast cancer;inflammatory breast cancer; breast ductal carcinoma; breast lobularcarcinoma; luminal A breast cancer; luminal B breast cancer; basal-likebreast cancer; HER2 positive (HER2+) breast cancer; HER2 negative(HER2−) breast cancer; Estrogen Receptor negative (ER−) breast cancer;Estrogen Receptor positive (ER+) breast cancer; Progesterone Receptornegative (PR−) breast cancer; Progesterone Receptor positive (PR+)breast cancer; ER positive (ER+) and PR positive (PR+) breast cancer; ERpositive (ER+) and PR negative (PR−) breast cancer; ER negative (ER−)and PR positive (PR+) breast cancer; ER positive (ER+) and HER2 negative(HER2−) breast cancer; ER−, PR−, and HER2− triple negative breast cancer(ER−, PR−, HER2−; TNBC); hormone receptor negative breast cancer (ER−and PR−); ER+, PR+, and HER2+ triple positive breast cancer (ER+, PR+,HER2+; TPBC); hepatocellular carcinoma (HCC); head and neck squamouscell carcinoma (HNSCC); oral tongue squamous cell carcinoma (OTSCC);sarcomas (e.g. epitheloid, rhabdoid and synovial); esophageal cancer;gastric cancer; ovarian cancer; pancreatic cancer; lung cancer;non-small cell lung carcinoma (NSCLC); small-cell lung carcinoma (SCLC);squamous cell carcinoma (SCC); head and neck cancer; head and necksquamous cell carcinoma (HNSCC); gastrointestinal cancer; largeintestinal cancer; small intestinal cancer; stomach cancer; coloncancer; colorectal cancer; bladder cancer; liver cancer; biliary tractcancer; urothelial cancer; endometrial cancer; cervical cancer; prostatecancer; mesothelioma; chordoma; renal cancer; renal cell carcinoma(RCC); brain cancer; neuroblastoma; glioblastoma; skin cancer; melanoma;basal cell carcinoma; merkel cell carcinoma; blood cancer; hematopoeticcancer; myeloma; multiple myeloma (MM); B cell malignancies; lymphoma; Bcell lymphoma; Hodgkin lymphoma; T cell lymphoma; leukemia; or acutelymphocytic leukemia (ALL). In certain embodiments, a secondary agent isselected from: a chemotherapeutic agent including, but not limited to,capecitabine (Xeloda), carboplatin, cisplatin, cyclophosphamide,docetaxel (Taxotere), doxorubicin, epirubicin (Ellence), eribulin(Halaven), fluorouracil (5-FU, Efudex), gemcitabine (Gemzar),ixabepilone (Ixempra), methotrexate (Rheumatrex, Trexall), paclitaxel(Taxol), or vinorelbine (Navelbine); a combination regiment including,but not limited to, AC (doxorubicin and cyclophosphamide), EC(epirubicin, cyclophosphamide), AC or EC (epirubicin andcyclophosphamide) followed by T (doxorubicin and cyclophosphamide,followed by paclitaxel or docetaxel), CAF (cyclophosphamide,doxorubicin, and 5-FU), CEF (cyclophosphamide, epirubicin, and 5-FU),CMF (cyclophosphamide, methotrexate, and 5-FU), TAC (docetaxel,doxorubicin, and cyclophosphamide), TC (docetaxel and cyclophosphamide),AC-TH (doxorubicin, cyclophosphamide, paclitaxel, trastuzumab), AC-THP(doxorubicin, cyclophosphamide, paclitaxel, trastuzumab, pertuzumab),TCHP (docetaxel, carboplatin, trastuzumab, pertuzumab), TCH (docetaxel,carboplatin, trastuzumab), or TH (paclitaxel, trastuzumab); hormonetherapy including, but not limited to, selective estrogen receptormodulators, tamoxifen, toremifene (Fareston), fulvestrant (Faslodex),goserelin (Zoladex), or leuprolide (Eligard, Lupron); aromataseinhibitors (AIs) including, but not limited to, anastrozole (Arimidex),exemestane (Aromasin), or letrozole (Femara); HER2-targeted therapyincluding, but not limited to, trastuzumab (Herceptin), lapatinib(TYKERB), pertuzumab (Perjeta), or neratinib (Nerlynx).

Certain embodiments are drawn to a combination of a compound targeted toMALAT1 as described herein and a secondary agent, such as a secondaryagent selected from: a chemotherapeutic agent including, but not limitedto, capecitabine (Xeloda), carboplatin, cisplatin, cyclophosphamide,docetaxel (Taxotere), doxorubicin, epirubicin (Ellence), eribulin(Halaven), fluorouracil (5-FU, Efudex), gemcitabine (Gemzar),ixabepilone (Ixempra), methotrexate (Rheumatrex, Trexall), paclitaxel(Taxol), or vinorelbine (Navelbine); a combination regiment including,but not limited to, AC (doxorubicin and cyclophosphamide), EC(epirubicin, cyclophosphamide), AC or EC (epirubicin andcyclophosphamide) followed by T (doxorubicin and cyclophosphamide,followed by paclitaxel or docetaxel), CAF (cyclophosphamide,doxorubicin, and 5-FU), CEF (cyclophosphamide, epirubicin, and 5-FU),CMF (cyclophosphamide, methotrexate, and 5-FU), TAC (docetaxel,doxorubicin, and cyclophosphamide), TC (docetaxel and cyclophosphamide),AC-TH (doxorubicin, cyclophosphamide, paclitaxel, trastuzumab), AC-THP(doxorubicin, cyclophosphamide, paclitaxel, trastuzumab, pertuzumab),TCHP (docetaxel, carboplatin, trastuzumab, pertuzumab), TCH (docetaxel,carboplatin, trastuzumab), or TH (paclitaxel, trastuzumab); hormonetherapy including, but not limited to, selective estrogen receptormodulators, tamoxifen, toremifene (Fareston), fulvestrant (Faslodex),goserelin (Zoladex), or leuprolide (Eligard, Lupron); aromataseinhibitors (AIs) including, but not limited to, anastrozole (Arimidex),exemestane (Aromasin), or letrozole (Femara); HER2-targeted therapyincluding, but not limited to, trastuzumab (Herceptin), lapatinib(TYKERB), pertuzumab (Perjeta), or neratinib (Nerlynx).

In certain embodiments the compound targeted to MALAT1 as describedherein and the secondary agent are used in combination treatment byadministering the two agents simultaneously, separately or sequentially.In certain embodiments the two agents are formulated as a fixed dosecombination product. In other embodiments the two agents are provided tothe patient as separate units which can then either be takensimultaneously or serially (sequentially).

In certain embodiments, a compound targeted to MALAT1 as describedherein is used in combination with an immunomodulatory agent such as ananti-PD-L1 antibody (or an antigen-binding fragment thereof), ananti-PD-1 antibody (or an antigen-binding fragment thereof), ananti-CTLA-4 antibody (or an antigen-binding fragment thereof) or an OX40agonist ((e.g., an OX40 ligand fusion protein, or an OX40 agonistantibody or antigen-binding fragment thereof).

In certain embodiments, a compound targeted to MALAT1 as describedherein is used in combination with an immune checkpoint inhibitor suchas an anti-PD-L1 antibody (or an antigen-binding fragment thereof), ananti-PD-1 antibody (or an antigen-binding fragment thereof), or ananti-CTLA-4 antibody (or an antigen-binding fragment thereof).

Anti-PD-L1 antibodies are known in the art. Exemplary anti-PD-L1antibodies include: MEDI4736 (durvalumab), MPDL3280A, BMS936559, 2.7A4,AMP-714, MDX-1105 and MPDL3280A (atezolizumab).

Anti-PD-1 antibodies are known in the art. Exemplary anti-PD-1antibodies include: nivolumab, pembrolizumab, pidilizumab, and AMP-514Anti-CTLA-4 antibodies are known in the art. Exemplary anti-CTLA-4antibodies include: tremelimumab and ipilimumab, also termed MDX-010 (orBMS-734016).

OX40 agonists and antibodies are known in the art. Exemplary OX40agonists and/or antibodies include: MEDI6383, 9B12 and MEDI0562.

In one embodiment, the combination includes the antisenseoligonucleotide Ionis 1158161 or a salt thereof, and at least oneimmunomodulator selected from the group consisting of: MEDI4736,MPDL3280A, BMS936559, 2.7A4, AMP-714, MDX-1105, nivolumab,pembrolizumab, pidilizumab, MPDL3280A, tremelimumab, ipilimumab,MEDI0562 and MEDI0562.

Certain Anti-PD-L1 Antibodies

Antibodies that specifically bind and inhibit PD-L1 are included in thepresent disclosure.

Durvalumab (MEDI4736) is an exemplary anti-PD-L1 antibody that isselective for a PD-L1 polypeptide and blocks the binding of PD-L1 to thePD-1 and CD80 receptors. Durvalumab can relieve PD-L1-mediatedsuppression of human T-cell activation in vitro and inhibits tumorgrowth in a xenograft model via a T-cell dependent mechanism.

Information regarding durvalumab (or fragments thereof) for use in themethods provided herein can be found in U.S. Pat. No. 8,779,108, thedisclosure of which is incorporated herein by reference in its entirety.The fragment crystallizable (Fc) domain of durvalumab contains a triplemutation in the constant domain of the IgG1 heavy chain that reducesbinding to the complement component C1q and the Fcγ receptorsresponsible for mediating antibody-dependent cell-mediated cytotoxicity(ADCC).

Durvalumab and antigen-binding fragments thereof for use in the methodsprovided herein comprises a heavy chain and a light chain or a heavychain variable region and a light chain variable region. In certainembodiments, MEDI4736 or an antigen-binding fragment thereof for use inthe methods provided herein comprises the variable heavy chain andvariable light chain CDR sequences of the 2.14H9OPT antibody asdisclosed in U.S. Pat. Nos. 8,779,108 and 9,493,565, which is hereinincorporated by reference in its entirety. There are numerous anti-PD-L1antibodies in the published literature that could feature in the presentdisclosure, including compounds in development and/or in clinical trialssuch as: durvalumab (MEDI4736), MPDL3280A, BMS936559, 2.7A4, AMP-714 andMDX-1105. Patent specifications disclosing anti-PD-L1 antibodies thatmay be useful in the present disclosure include: U.S. Pat. Nos.7,943,743; 8,383,796; 9,102,725; 9,273,135 (BMS/Medarex), US2006/0153841(Dana Farber), US2011/0271358 (Dana Farber), U.S. Pat. Nos. 8,552,154and 9,102,727 (Dana Farber), U.S. Pat. No. 8,217,149 (Genentech),including issued U.S. Pat. No. 8,217,149, US2012/0039906 (INSERM),US2016/0031990 (Amplimmune), U.S. Pat. No. 8,779,108 (MedImmune—fordurvalumab/MEDI4726 and 2.7A4), US2014/0044738 (Amplimmune—for AMP-714)and US2010/0285039 (John's Hopkins University). Each of thesedisclosures is herein incorporated by reference in its entirety.

Certain Anti-CTLA-4 Antibodies

Antibodies that specifically bind CTLA-4 and inhibit CTLA-4 activity areuseful for enhancing an anti-tumor immune response. Informationregarding tremelimumab (or antigen-binding fragments thereof) for use inthe methods provided herein can be found in U.S. Pat. No. 6,682,736(where it is referred to as 11.2.1), the disclosure of which isincorporated herein by reference in its entirety. Tremelimumab (alsoknown as CP-675,206, CP-675, CP-675206, and ticilimumab) is a human IgG2monoclonal antibody that is highly selective for CTLA-4 and blocksbinding of CTLA-4 to CD80 (B7.1) and CD86 (B7.2). It has been shown toresult in immune activation in vitro and some patients treated withtremelimumab have shown tumor regression.

Tremelimumab for use in the methods provided herein comprises a heavychain and a light chain or a heavy chain variable region and a lightchain variable region. In a specific aspect, tremelimumab or anantigen-binding fragment thereof for use in the methods provided hereincomprises a light chain variable region comprising the amino acidsequences shown herein above and a heavy chain variable regioncomprising the amino acid sequence shown herein above. In a specificaspect, tremelimumab or an antigen-binding fragment thereof for use inthe methods provided herein comprises a heavy chain variable region anda light chain variable region, wherein the heavy chain variable regioncomprises the Kabat-defined CDR1, CDR2, and CDR3 sequences shown hereinabove, and wherein the light chain variable region comprises theKabat-defined CDR1, CDR2, and CDR3 sequences shown herein above. Thoseof ordinary skill in the art would easily be able to identifyChothia-defined, Abm-defined or other CDR definitions known to those ofordinary skill in the art. In a specific aspect, tremelimumab or anantigen-binding fragment thereof for use in the methods provided hereincomprises the variable heavy chain and variable light chain CDRsequences of the 11.2.1 antibody as disclosed in U.S. Pat. No.6,682,736, which is herein incorporated by reference in its entirety.

Other anti-CTLA-4 antibodies are described, for example, in US20070243184. In one embodiment, the anti-CTLA-4 antibody is Ipilimumab,also termed MDX-010; BMS-734016.

Certain OX40 Agonists

OX40 agonists interact with the OX40 receptor on CD4+ T-cells during, orshortly after, priming by an antigen resulting in an increased responseof the CD4+ T-cells to the antigen. An OX40 agonist interacting with theOX40 receptor on antigen specific CD4+ T-cells can increase T cellproliferation as compared to the response to antigen alone. The elevatedresponse to the antigen can be maintained for a period of timesubstantially longer than in the absence of an OX40 agonist. Thus,stimulation via an OX40 agonist enhances the antigen specific immuneresponse by boosting T-cell recognition of antigens, e.g., tumor cells.OX40 agonists are described, for example, in U.S. Pat. Nos. 6,312,700,7,504,101, 7,622,444, and 7,959,925, which are incorporated herein byreference in their entireties. Methods of using such agonists in cancertreatment are described, for example, in US2015/0098942 and inUS2015/0157710, each of which are incorporated herein by reference inits entirety.

OX40 agonists include, but are not limited to OX40 binding molecules,e.g., binding polypeptides, e.g., OX40 ligand (“OX40L”) or anOX40-binding fragment, variant, or derivative thereof, such as solubleextracellular ligand domains and OX40L fusion proteins, and anti-OX40antibodies (for example, monoclonal antibodies such as humanizedmonoclonal antibodies), or an antigen-binding fragment, variant orderivative thereof. Examples of anti-OX40 monoclonal antibodies aredescribed, for example, in U.S. Pat. Nos. 5,821,332 and 6,156,878, thedisclosures of which are incorporated herein by reference in theirentireties. In certain embodiments, the anti-OX40 monoclonal antibody is9B12, or an antigen-binding fragment, variant, or derivative thereof, asdescribed in Weinberg, A. D., et al. J Immunother 29, 575-585 (2006),which is incorporated herein by reference in its entirety. In anotherembodiment, an OX40 antibody is MEDI0562 as described in US2016/0137740.

In certain embodiments, the antibody which specifically binds to OX40,or an antigen-binding fragment thereof binds to the same OX40 epitope asmAb 9B12. An example of a humanized OX40 antibody is described by Morriset al., Mol Immunol. May 2007; 44(12): 3112-3121. 9B12 is a murine IgG1,anti-OX40 mAb directed against the extracellular domain of human OX40(CD134) (Weinberg, A. D., et al. J Immunother 29, 575-585 (2006)). Itwas selected from a panel of anti-OX40 monoclonal antibodies because ofits ability to elicit an agonist response for OX40 signaling, stability,and for its high level of production by the hybridoma. For use inclinical applications, 9B12 mAb is equilibrated with phosphate bufferedsaline, pH 7.0, and its concentration is adjusted to 5.0 mg/ml bydiafiltration.

“OX40 ligand” (“OX40L”) (also variously termed tumor necrosis factorligand superfamily member 4, gp34, TAX transcriptionally-activatedglycoprotein-1, and CD252) is found largely on antigen presenting cells(APCs), and can be induced on activated B cells, dendritic cells (DCs),Langerhans cells, plamacytoid DCs, and macrophages (Croft, M., (2010)Ann Rev Immunol 28:57-78). Other cells, including activated T cells, NKcells, mast cells, endothelial cells, and smooth muscle cells canexpress OX40L in response to inflammatory cytokines (Id.). OX40Lspecifically binds to the OX40 receptor. The human protein is describedin U.S. Pat. No. 6,156,878. The mouse OX40L is described in U.S. Pat.No. 5,457,035. OX40L is expressed on the surface of cells and includesan intracellular, a transmembrane and an extracellular receptor-bindingdomain. A functionally active soluble form of OX40L can be produced bydeleting the intracellular and transmembrane domains as described, e.g.,in U.S. Pat. Nos. 5,457,035; 6,312,700; 6,156,878; 6,242,566; 6,528,055;6,528,623; 7,098,184; and 7,125,670, the disclosures of which areincorporated herein for all purposes. A functionally active form ofOX40L is a form that retains the capacity to bind specifically to OX40,that is, that possesses an OX40 “receptor binding domain.” An example isamino acids 51 to 183 of human OX40L. Methods of determining the abilityof an OX40L molecule or derivative to bind specifically to OX40 arediscussed below. Methods of making and using OX40L and its derivatives(such as derivatives that include an OX40 binding domain) are describedin U.S. Pat. Nos. 6,156,878; 6,242,566; 6,528,055; 6,528,623; 7,098,184;and 7,125,670, which also describe proteins comprising the soluble formof OX40L linked to other peptides, such as human immunoglobulin (“Ig”)Fc regions, that can be produced to facilitate purification of OX40ligand from cultured cells, or to enhance the stability of the moleculeafter in vivo administration to a mammal (see also, U.S. Pat. Nos.5,457,035 and 7,959,925, both of which are incorporated by referenceherein in their entireties).

Also included within the definition of OX40L are OX40 ligand variantswhich vary in amino acid sequence from naturally occurring OX40 ligandmolecules but which retain the ability to specifically bind to an OX40receptor. Such variants are described in U.S. Pat. Nos. 5,457,035;6,156,878; 6,242,566; 6,528,055; 6,528,623; 7,098,184; and 7,125,670. Ina related embodiment, a mutant of OX40L which has lost the ability tospecifically bind to OX40, for example amino acids 51 to 183, in whichthe phenylalanine at position 180 of the receptor-binding domain ofhuman OX40L has been replaced with alanine (F180A) is used.

OX40 agonists include a fusion protein in which one or more domains ofOX40L is covalently linked to one or more additional protein domains.Exemplary OX40L fusion proteins that can be used as OX40 agonists aredescribed in U.S. Pat. No. 6,312,700, the disclosure of which isincorporated herein by reference in its entirety. In one embodiment, anOX40 agonist includes an OX40L fusion polypeptide that self-assemblesinto a multimeric (e.g., trimeric or hexameric) OX40L fusion protein.Such fusion proteins are described, e.g., in U.S. Pat. No. 7,959,925,which is incorporated by reference herein in its entirety. Themultimeric OX40L fusion protein exhibits increased efficacy in enhancingantigen specific immune response in a subject, particularly a humansubject, due to its ability to spontaneously assemble into highly stabletrimers and hexamers.

In another embodiment, an OX40 agonist capable of assembling into amultimeric form includes a fusion polypeptide comprising in anN-terminal to C-terminal direction: an immunoglobulin domain, whereinthe immunoglobulin domain includes an Fc domain, a trimerization domain,wherein the trimerization domain includes a coiled coil trimerizationdomain, and a receptor binding domain, wherein the receptor bindingdomain is an OX40 receptor binding domain, e.g., an OX40L or anOX40-binding fragment, variant, or derivative thereof, where the fusionpolypeptide can self-assemble into a trimeric fusion protein. In oneaspect, an OX40 agonist capable of assembling into a multimeric form iscapable of binding to the OX40 receptor and stimulating at least oneOX40 mediated activity. In certain aspects, the OX40 agonist includes anextracellular domain of OX40 ligand.

The trimerization domain of an OX40 agonist capable of assembling into amultimeric form serves to promote self-assembly of individual OX40Lfusion polypeptide molecules into a trimeric protein. Thus, an OX40Lfusion polypeptide with a trimerization domain self-assembles into atrimeric OX40L fusion protein. In one aspect, the trimerization domainis an isoleucine zipper domain or other coiled coli polypeptidestructure. Exemplary coiled coil trimerization domains include: TRAF2(GENBANK® Accession No. Q12933, amino acids 299-348; Thrombospondin 1(Accession No. P07996, amino acids 291-314; Matrilin-4 (Accession No.095460, amino acids 594-618; CMP (matrilin-1) (Accession No. NP-002370,amino acids 463-496; HSF1 (Accession No. AAX42211, amino acids 165-191;and Cubilin (Accession No. NP-001072, amino acids 104-138. In certainspecific aspects, the trimerization domain includes a TRAF2trimerization domain, a Matrilin-4 trimerization domain, or acombination thereof.

OX40L FP is a human OX40 ligand IgG4P fusion protein that specificallybinds to, and triggers signaling by, the human OX40 receptor, a memberof the TNFR superfamily. OX40L FP is also disclosed in US2016/0024176,incorporated herein by reference in its entirety. OX40L FP is composedof three distinct domains: (1) human OX40 ligand extracellular receptorbinding domains (RBDs) that form homotrimers and bind the OX40 receptor;(2) isoleucine zipper trimerization domains derived from TNFR-associatedfactor 2 that stabilize the homotrimeric structure of the OX40 ligandRBDs; and (3) human IgG4 fragment crystallizable gamma (Fcγ) domainsthat facilitate Fcγ receptor clustering of the fusion protein when boundto OX40 receptors, and contain a serine to proline substitution atposition 228 (according to EU numbering) in the hinge regions (IgG4P) topromote stability of two sets of OX40 ligand RBD homotrimers. The IgG4PFc domain is fused directly to an isoleucine zipper trimerization domainderived from amino acid residues 310-349 of human tumor necrosis factor2 (TRAF2). Fused to the c-terminus of the TRAF2 domain are amino acidresidues 51-183 of the extracellular receptor binding domain (RBD) ofhuman OX40L (gene name TNFSF4). The TRAF2 domain stabilizes thehomotrimeric structure of OX40L RBDs to enable OX40 binding andactivation, while the IgG4P Fc domain confers serum stability,dimerization of OX40L trimers, and facilitates Fcγ receptor clusteringof the hexameric fusion protein. One OX40L FP variant possesses aphenylalanine (F) to alanine (A) mutation at the amino acidcorresponding to position 180 in OX40L. Another OX40L FP variant has theIgG4P Fc domain replaced with a human IgG1 Fc domain. In particularembodiments, the OX40 agonist for use in the present disclosure is oneof the OX40L FP variants.

In particular embodiments, the OX40 agonist for use in the presentdisclosure has been modified to increase its serum half-life. Forexample, the serum half-life of an OX40 agonist can be increased byconjugation to a heterologous molecule such as serum albumin, anantibody Fc region, or PEG. In certain embodiments, OX40 agonists can beconjugated to other therapeutic agents or toxins to formimmunoconjugates and/or fusion proteins. In certain embodiments, theOX40 agonist can be formulated so as to facilitate administration andpromote stability of the active agent.

Antibody Derivatives

Antibodies for use in the present disclosure (e.g., anti-CTLA-4,anti-PD-L1, anti-PD-1, anti-OX40) may include variants of thesesequences that retain the ability to specifically bind their targets.Such variants may be derived from the sequence of these antibodies by askilled artisan using techniques well known in the art. For example,amino acid substitutions, deletions, or additions, can be made in theFRs and/or in the CDRs. While changes in the FRs are usually designed toimprove stability and immunogenicity of the antibody, changes in theCDRs are typically designed to increase affinity of the antibody for itstarget. Variants of FRs also include naturally occurring immunoglobulinallotypes. Such affinity-increasing changes may be determinedempirically by routine techniques that involve altering the CDR andtesting the affinity antibody for its target. For example, conservativeamino acid substitutions can be made within any one of the disclosedCDRs. Various alterations can be made according to the methods describedin Antibody Engineering, 2nd ed., Oxford University Press, ed.Borrebaeck, 1995. These include but are not limited to nucleotidesequences that are altered by the substitution of different codons thatencode a functionally equivalent amino acid residue within the sequence,thus producing a “silent” change. For example, the nonpolar amino acidsinclude alanine, leucine, isoleucine, valine, proline, phenylalanine,tryptophan, and methionine. The polar neutral amino acids includeglycine, serine, threonine, cysteine, tyrosine, asparagine, andglutamine. The positively charged (basic) amino acids include arginine,lysine, and histidine. The negatively charged (acidic) amino acidsinclude aspartic acid and glutamic acid.

Derivatives and analogs of antibodies of the present disclosure can beproduced by various techniques well known in the art, includingrecombinant and synthetic methods (Maniatis (1990) Molecular Cloning, ALaboratory Manual, 2nd ed., Cold Spring Harbor Laboratory, Cold SpringHarbor, N.Y., and Bodansky et al. (1995) The Practice of PeptideSynthesis, 2nd ed., Spring Verlag, Berlin, Germany). Analogous shufflingor combinatorial techniques are also disclosed by Stemmer (Nature (1994)370: 389-391), who describes the technique in relation to a β-lactamasegene but observes that the approach may be used for the generation ofantibodies.

One may generate novel VH or VL regions carrying one or more sequencesderived from the sequences disclosed herein using random mutagenesis ofone or more selected VH and/or VL genes. One such technique, error-pronePCR, is described by Gram et al. (Proc. Nat. Acad. Sci. U.S.A. (1992)89: 3576-3580).

Another method that may be used is to direct mutagenesis to CDRs of VHor VL genes. Such techniques are disclosed by Barbas et al. (Proc. Nat.Acad. Sci. U.S.A. (1994) 91: 3809-3813) and Schier et al. (J. Mol. Biol.(1996) 263: 551-567).

Similarly, one or more, or all three CDRs may be grafted into arepertoire of VH or VL domains, which are then screened for anantigen-binding fragment specific for CTLA-4 or PD-L1.

A portion of an immunoglobulin variable domain will comprise at leastone of the CDRs substantially as set out herein and, optionally,intervening framework regions from the scFv fragments as set out herein.The portion may include at least about 50% of either or both of FR1 andFR4, the 50% being the C-terminal 50% of FR1 and the N-terminal 50% ofFR4. Additional residues at the N-terminal or C-terminal end of thesubstantial part of the variable domain may be those not normallyassociated with naturally occurring variable domain regions. Forexample, construction of antibodies by recombinant DNA techniques mayresult in the introduction of N- or C-terminal residues encoded bylinkers introduced to facilitate cloning or other manipulation steps.Other manipulation steps include the introduction of linkers to joinvariable domains to further protein sequences including immunoglobulinheavy chain constant regions, other variable domains (for example, inthe production of diabodies), or proteinaceous labels as discussed infurther detail below.

A skilled artisan will recognize that antibodies for use in the presentdisclosure may comprise antigen-binding fragments containing only asingle CDR from either VL or VH domain. Either one of the single chainspecific binding domains can be used to screen for complementary domainscapable of forming a two-domain specific antigen-binding fragmentcapable of, for example, binding to CTLA-4 and PD-L1.

Antibodies for use in the present disclosure described herein can belinked to another functional molecule, e.g., another peptide or protein(albumin, another antibody, etc.). For example, the antibodies can belinked by chemical cross-linking or by recombinant methods. Theantibodies may also be linked to one of a variety of nonproteinaceouspolymers, e.g., polyethylene glycol, polypropylene glycol, orpolyoxyalkylenes, in the manner set forth in U.S. Pat. Nos. 4,640,835;4,496,689; 4,301,144; 4,670,417; 4,791,192; or 4,179,337. The antibodiescan be chemically modified by covalent conjugation to a polymer, forexample, to increase their circulating half-life. Exemplary polymers andmethods to attach them are also shown in U.S. Pat. Nos. 4,766,106;4,179,337; 4,495,285, and 4,609,546.

The antibodies may also be altered to have a glycosylation pattern thatdiffers from the native pattern. For example, one or more carbohydratemoieties can be deleted and/or one or more glycosylation sites added tothe original antibody. Addition of glycosylation sites to the presentlydisclosed antibodies may be accomplished by altering the amino acidsequence to contain glycosylation site consensus sequences known in theart. Another means of increasing the number of carbohydrate moieties onthe antibodies is by chemical or enzymatic coupling of glycosides to theamino acid residues of the antibody. Such methods are described in WO87/05330, and in Aplin et al. (1981) CRC Crit. Rev. Biochem., 22:259-306. Removal of any carbohydrate moieties from the antibodies may beaccomplished chemically or enzymatically, for example, as described byHakimuddin et al. (1987) Arch. Biochem. Biophys., 259: 52; and Edge etal. (1981) Anal. Biochem., 118: 131 and by Thotakura et al. (1987) Meth.Enzymol., 138: 350. The antibodies may also be tagged with a detectable,or functional, label. Detectable labels include radiolabels such as 1311or 99Tc, which may also be attached to antibodies using conventionalchemistry. Detectable labels also include enzyme labels such ashorseradish peroxidase or alkaline phosphatase. Detectable labelsfurther include chemical moieties such as biotin, which may be detectedvia binding to a specific cognate detectable moiety, e.g., labeledavidin.

Antibodies, in which CDR sequences differ only insubstantially fromthose set forth herein are encompassed within the scope of this presentdisclosure. Typically, an amino acid is substituted by a related aminoacid having similar charge, hydrophobic, or stereochemicalcharacteristics. Such substitutions would be within the ordinary skillsof an artisan. Unlike in CDRs, more substantial changes can be made inFRs without adversely affecting the binding properties of an antibody.Changes to FRs include, but are not limited to, humanizing a non-humanderived or engineering certain framework residues that are important forantigen contact or for stabilizing the binding site, e.g., changing theclass or subclass of the constant region, changing specific amino acidresidues which might alter the effector function such as Fc receptorbinding, e.g., as described in U.S. Pat. Nos. 5,624,821 and 5,648,260and Lund et al. (1991) J. Immun. 147: 2657-2662 and Morgan et al. (1995)Immunology 86: 319-324, or changing the species from which the constantregion is derived.

One of skill in the art will appreciate that the modifications describedabove are not all-exhaustive, and that many other modifications would beobvious to a skilled artisan in light of the teachings of the presentdisclosure.

Certain Compounds

In certain embodiments, compounds described herein can be antisensecompounds. In certain embodiments, the antisense compound comprises orconsists of an oligomeric compound. In certain embodiments, theoligomeric compound comprises a modified oligonucleotide. In certainembodiments, the modified oligonucleotide has a nucleobase sequencecomplementary to that of a target nucleic acid.

In certain embodiments, a compound described herein comprises orconsists of a modified oligonucleotide. In certain embodiments, themodified oligonucleotide has a nucleobase sequence complementary to thatof a target nucleic acid.

In certain embodiments, a compound or antisense compound issingle-stranded. Such a single-stranded compound or antisense compoundcomprises or consists of an oligomeric compound. In certain embodiments,such an oligomeric compound comprises or consists of an oligonucleotideand optionally a conjugate group. In certain embodiments, theoligonucleotide is an antisense oligonucleotide. In certain embodiments,the oligonucleotide is modified. In certain embodiments, theoligonucleotide of a single-stranded antisense compound or oligomericcompound comprises a self-complementary nucleobase sequence.

In certain embodiments, compounds are double-stranded. Suchdouble-stranded compounds comprise a first modified oligonucleotidehaving a region complementary to a target nucleic acid and a secondmodified oligonucleotide having a region complementary to the firstmodified oligonucleotide. In certain embodiments, the modifiedoligonucleotide is an RNA oligonucleotide. In such embodiments, thethymine nucleobase in the modified oligonucleotide is replaced by auracil nucleobase. In certain embodiments, compound comprises aconjugate group. In certain embodiments, one of the modifiedoligonucleotides is conjugated. In certain embodiments, both themodified oligonucleotides are conjugated. In certain embodiments, thefirst modified oligonucleotide is conjugated. In certain embodiments,the second modified oligonucleotide is conjugated. In certainembodiments, the first modified oligonucleotide consists of 12-30 linkednucleosides and the second modified oligonucleotide consists of 12-30linked nucleosides. In certain embodiments, one of the modifiedoligonucleotides has a nucleobase sequence comprising at least 8contiguous nucleobases of any of SEQ ID NOs: 36-2646 or 2664-2813. Incertain embodiments, one of the modified oligonucleotides has anucleobase sequence comprising at least 8 contiguous nucleobases of anyof SEQ ID NOs: 2-10.

In certain embodiments, antisense compounds are double-stranded. Suchdouble-stranded antisense compounds comprise a first oligomeric compoundhaving a region complementary to a target nucleic acid and a secondoligomeric compound having a region complementary to the firstoligomeric compound. The first oligomeric compound of such doublestranded antisense compounds typically comprises or consists of amodified oligonucleotide and optionally a conjugate group. Theoligonucleotide of the second oligomeric compound of suchdouble-stranded antisense compound may be modified or unmodified. Eitheror both oligomeric compounds of a double-stranded antisense compound maycomprise a conjugate group. The oligomeric compounds of double-strandedantisense compounds may include non-complementary overhangingnucleosides.

Examples of single-stranded and double-stranded compounds include butare not limited to oligonucleotides, siRNAs, microRNA targetingoligonucleotides, and single-stranded RNAi compounds, such as smallhairpin RNAs (shRNAs), single-stranded siRNAs (ssRNAs), and microRNAmimics.

In certain embodiments, a compound described herein has a nucleobasesequence that, when written in the 5′ to 3′ direction, comprises thereverse complement of the target segment of a target nucleic acid towhich it is targeted.

In certain embodiments, a compound described herein comprises anoligonucleotide consisting of 10 to 30 linked subunits. In certainembodiments, a compound described herein comprises an oligonucleotideconsisting of 12 to 30 linked subunits. In certain embodiments, acompound described herein comprises an oligonucleotide consisting of 12to 22 linked subunits. In certain embodiments, a compound describedherein comprises an oligonucleotide consisting of 14 to 30 linkedsubunits. In certain embodiments, compound described herein comprises anoligonucleotide consisting of 14 to 20 linked subunits. In certainembodiments, a compound described herein comprises an oligonucleotideconsisting of 15 to 30 linked subunits. In certain embodiments, acompound described herein comprises an oligonucleotide consisting of 15to 20 linked subunits. In certain embodiments, a compound describedherein comprises an oligonucleotide consisting of 16 to 30 linkedsubunits. In certain embodiments, a compound described herein comprisesan oligonucleotide consisting of 16 to 20 linked subunits. In certainembodiments, a compound described herein comprises an oligonucleotideconsisting of 17 to 30 linked subunits. In certain embodiments, acompound described herein comprises an oligonucleotide consisting of 17to 20 linked subunits. In certain embodiments, a compound describedherein comprises an oligonucleotide consisting of 18 to 30 linkedsubunits. In certain embodiments, a compound described herein comprisesan oligonucleotide consisting of 18 to 21 linked subunits. In certainembodiments, a compound described herein comprises an oligonucleotideconsisting of 18 to 20 linked subunits. In certain embodiments, acompound described herein comprises an oligonucleotide consisting of 20to 30 linked subunits. In other words, such oligonucleotides consist of12 to 30 linked subunits, 14 to 30 linked subunits, 14 to 20 subunits,15 to 30 subunits, 15 to 20 subunits, 16 to 30 subunits, 16 to 20subunits, 17 to 30 subunits, 17 to 20 subunits, 18 to 30 subunits, 18 to20 subunits, 18 to 21 subunits, 20 to 30 subunits, or 12 to 22 linkedsubunits, respectively. In certain embodiments, a compound describedherein comprises an oligonucleotide consisting of 14 linked subunits. Incertain embodiments, a compound described herein comprises anoligonucleotide consisting of 16 linked subunits. In certainembodiments, a compound described herein comprises an oligonucleotideconsisting of 17 linked subunits. In certain embodiments, compounddescribed herein comprises an oligonucleotide consisting of 18 linkedsubunits. In certain embodiments, a compound described herein comprisesan oligonucleotide consisting of 19 linked subunits. In certainembodiments, a compound described herein comprises an oligonucleotideconsisting of 20 linked subunits. In other embodiments, a compounddescribed herein comprises an oligonucleotide consisting of 8 to 80, 12to 50, 13 to 30, 13 to 50, 14 to 30, 14 to 50, 15 to 30, 15 to 50, 16 to30, 16 to 50, 17 to 30, 17 to 50, 18 to 22, 18 to 24, 18 to 30, 18 to50, 19 to 22, 19 to 30, 19 to 50, or 20 to 30 linked subunits. Incertain such embodiments, the compound described herein comprises anoligonucleotide consisting of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54,55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, or 80 linked subunits, or a range defined byany two of the above values. In some embodiments the linked subunits arenucleotides, nucleosides, or nucleobases.

In certain embodiments, the compound may further comprise additionalfeatures or elements, such as a conjugate group, that are attached tothe oligonucleotide. In certain embodiments, such compounds areantisense compounds. In certain embodiments, such compounds areoligomeric compounds. In embodiments where a conjugate group comprises anucleoside (i.e. a nucleoside that links the conjugate group to theoligonucleotide), the nucleoside of the conjugate group is not countedin the length of the oligonucleotide.

In certain embodiments, compounds may be shortened or truncated. Forexample, a single subunit may be deleted from the 5′ end (5′truncation), or alternatively from the 3′ end (3′ truncation). Ashortened or truncated compound targeted to an MALAT1 nucleic acid mayhave two subunits deleted from the 5′ end, or alternatively may have twosubunits deleted from the 3′ end, of the compound. Alternatively, thedeleted nucleosides may be dispersed throughout the compound.

When a single additional subunit is present in a lengthened compound,the additional subunit may be located at the 5′ or 3′ end of thecompound. When two or more additional subunits are present, the addedsubunits may be adjacent to each other, for example, in a compoundhaving two subunits added to the 5′ end (5′ addition), or alternativelyto the 3′ end (3′ addition), of the compound. Alternatively, the addedsubunits may be dispersed throughout the compound.

It is possible to increase or decrease the length of a compound, such asan oligonucleotide, and/or introduce mismatch bases without eliminatingactivity (Woolf et al. Proc. Natl. Acad. Sci. USA 1992, 89:7305-7309;Gautschi et al. J. Natl. Cancer Inst. March 2001, 93:463-471; Maher andDolnick Nuc. Acid. Res. 1998, 16:3341-3358). However, seemingly smallchanges in oligonucleotide sequence, chemistry and motif can make largedifferences in one or more of the many properties required for clinicaldevelopment (Seth et al. J. Med. Chem. 2009, 52, 10; Egli et al. J. Am.Chem. Soc. 2011, 133, 16642).

In certain embodiments, compounds described herein are interfering RNAcompounds (RNAi), which include double-stranded RNA compounds (alsoreferred to as short-interfering RNA or siRNA) and single-stranded RNAicompounds (or ssRNA). Such compounds work at least in part through theRISC pathway to degrade and/or sequester a target nucleic acid (thus,include microRNA/microRNA-mimic compounds). As used herein, the termsiRNA is meant to be equivalent to other terms used to describe nucleicacid molecules that are capable of mediating sequence specific RNAi, forexample short interfering RNA (siRNA), double-stranded RNA (dsRNA),micro-RNA (miRNA), short hairpin RNA (shRNA), short interferingoligonucleotide, short interfering nucleic acid, short interferingmodified oligonucleotide, chemically modified siRNA,post-transcriptional gene silencing RNA (ptgsRNA), and others. Inaddition, as used herein, the term “RNAi” is meant to be equivalent toother terms used to describe sequence specific RNA interference, such aspost transcriptional gene silencing, translational inhibition, orepigenetics.

In certain embodiments, a compound described herein can comprise any ofthe oligonucleotide sequences targeted to MALAT1 described herein. Incertain embodiments, the compound can be double-stranded. In certainembodiments, the compound comprises a first strand comprising at leastan 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguousnucleobase portion of any one of SEQ ID NOs: 2-10 or 36-2813 and asecond strand. In certain embodiments, the compound comprises a firststrand comprising the nucleobase sequence of any one of SEQ ID NOs: 2-10or 36-2813 and a second strand. In certain embodiments, the compoundcomprises ribonucleotides in which the first strand has uracil (U) inplace of thymine (T) in any one of SEQ ID NOs: 2-10 or 36-2813. Incertain embodiments, the compound comprises (i) a first strandcomprising a nucleobase sequence complementary to the site on MALAT1 towhich any of SEQ ID NOs: 2-10 or 36-2813 is targeted, and (ii) a secondstrand. In certain embodiments, the compound comprises a first strandcomprising at least an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or20 contiguous nucleobase portion of any one of SEQ ID NOs: 2-10 and asecond strand. In certain embodiments, the compound comprises a firststrand comprising the nucleobase sequence of any one of SEQ ID NOs: 2-10and a second strand. In certain embodiments, the compound comprisesribonucleotides in which the first strand has uracil (U) in place ofthymine (T) in any one of SEQ ID NOs: 2-10. In certain embodiments, thecompound comprises (i) a first strand comprising a nucleobase sequencecomplementary to the site on MALAT1 to which any of SEQ ID NOs: 2-10 istargeted, and (ii) a second strand. In certain embodiments, the compoundcomprises one or more modified nucleotides in which the 2′ position inthe sugar contains a halogen (such as fluorine group; 2′-F) or containsan alkoxy group (such as a methoxy group; 2′-OMe). In certainembodiments, the compound comprises at least one 2′-F sugar modificationand at least one 2′-OMe sugar modification. In certain embodiments, theat least one 2′-F sugar modification and at least one 2′-OMe sugarmodification are arranged in an alternating pattern for at least 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20contiguous nucleobases along a strand of the dsRNA compound. In certainembodiments, the compound comprises one or more linkages betweenadjacent nucleotides other than a naturally-occurring phosphodiesterlinkage. Examples of such linkages include phosphoramide,phosphorothioate, and phosphorodithioate linkages. The compounds mayalso be chemically modified nucleic acid molecules as taught in U.S.Pat. No. 6,673,661. In other embodiments, the compound contains one ortwo capped strands, as disclosed, for example, by WO 00/63364, filedApr. 19, 2000.

In certain embodiments, the first strand of the compound is an siRNAguide strand and the second strand of the compound is an siRNA passengerstrand. In certain embodiments, the second strand of the compound iscomplementary to the first strand. In certain embodiments, each strandof the compound consisting of 16, 17, 18, 19, 20, 21, 22, or 23 linkednucleosides. In certain embodiments, the first or second strand of thecompound can comprise a conjugate group.

In certain embodiments, a compound described herein can comprise any ofthe oligonucleotide sequences targeted to MALAT1 described herein. Incertain embodiments, the compound is single stranded. In certainembodiments, such a compound is a single-stranded RNAi (ssRNAi)compound. In certain embodiments, the compound comprises at least an 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobaseportion of any one of SEQ ID NOs: 2-10 or 36-2813. In certainembodiments, the compound comprises the nucleobase sequence of any oneof SEQ ID NOs: 2-10 or 36-2813. In certain embodiments, the compoundcomprises ribonucleotides in which uracil (U) is in place of thymine (T)in any one of SEQ ID NOs: 2-10 or 36-2813. In certain embodiments, thecompound comprises a nucleobase sequence complementary to the site onMALAT1 to which any of SEQ ID NOs: 2-10 or 36-2813 is targeted. Incertain embodiments, the compound comprises at least an 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobase portion ofany one of SEQ ID NOs: 2-10. In certain embodiments, the compoundcomprises the nucleobase sequence of any one of SEQ ID NOs: 2-10. Incertain embodiments, the compound comprises ribonucleotides in whichuracil (U) is in place of thymine (T) in any one of SEQ ID NOs: 2-10. Incertain embodiments, the compound comprises a nucleobase sequencecomplementary to the site on MALAT1 to which any of SEQ ID NOs: 2-10 istargeted. In certain embodiments, the compound comprises one or moremodified nucleotides in which the 2′ position in the sugar contains ahalogen (such as fluorine group; 2′-F) or contains an alkoxy group (suchas a methoxy group; 2′-OMe). In certain embodiments, the compoundcomprises at least one 2′-F sugar modification and at least one 2′-OMesugar modification. In certain embodiments, the at least one 2′-F sugarmodification and at least one 2′-OMe sugar modification are arranged inan alternating pattern for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobases along a strandof the compound. In certain embodiments, the compound comprises one ormore linkages between adjacent nucleotides other than anaturally-occurring phosphodiester linkage. Examples of such linkagesinclude phosphoramide, phosphorothioate, and phosphorodithioatelinkages. The compounds may also be chemically modified nucleic acidmolecules as taught in U.S. Pat. No. 6,673,661. In other embodiments,the compound contains a capped strand, as disclosed, for example, by WO00/63364, filed Apr. 19, 2000. In certain embodiments, the compoundconsists of 16, 17, 18, 19, 20, 21, 22, or 23 linked nucleosides. Incertain embodiments, the compound can comprise a conjugate group.

In certain embodiments, compounds described herein comprise modifiedoligonucleotides. Certain modified oligonucleotides have one or moreasymmetric center and thus give rise to enantiomers, diastereomers, andother stereoisomeric configurations that may be defined, in terms ofabsolute stereochemistry, as (R) or (S), as a or β such as for sugaranomers, or as (D) or (L) such as for amino acids etc. Included in themodified oligonucleotides provided herein are all such possible isomers,including their racemic and optically pure forms, unless specifiedotherwise. Likewise, all cis- and trans-isomers and tautomeric forms arealso included.

The compounds described herein include variations in which one or moreatoms are replaced with a non-radioactive isotope or radioactive isotopeof the indicated element. For example, compounds herein that comprisehydrogen atoms encompass all possible deuterium substitutions for eachof the ¹H hydrogen atoms. Isotopic substitutions encompassed by thecompounds herein include but are not limited to: ²H or ³H in place of¹H, ¹³C or ¹⁴C in place of ¹⁵N in place of ¹⁴N, ¹⁷O or ¹⁸O in place of¹⁶O, and ³³S, ³⁴S, ³⁵S, or ³⁶S in place of ³²S. In certain embodiments,non-radioactive isotopic substitutions may impart new properties on thecompound that are beneficial for use as a therapeutic or research tool.In certain embodiments, radioactive isotopic substitutions may make thecompound suitable for research or diagnostic purposes, such as animaging assay.

Certain Mechanisms

In certain embodiments, compounds described herein comprise or consistof modified oligonucleotides. In certain embodiments, compoundsdescribed herein are antisense compounds. In certain embodiments,compounds comprise oligomeric compounds. In certain embodiments,compounds described herein are capable of hybridizing to a targetnucleic acid, resulting in at least one antisense activity. In certainembodiments, compounds described herein selectively affect one or moretarget nucleic acid. Such compounds comprise a nucleobase sequence thathybridizes to one or more target nucleic acid, resulting in one or moredesired antisense activity and does not hybridize to one or morenon-target nucleic acid or does not hybridize to one or more non-targetnucleic acid in such a way that results in a significant undesiredantisense activity.

In certain antisense activities, hybridization of a compound describedherein to a target nucleic acid results in recruitment of a protein thatcleaves the target nucleic acid. For example, certain compoundsdescribed herein result in RNase H mediated cleavage of the targetnucleic acid. RNase H is a cellular endonuclease that cleaves the RNAstrand of an RNA:DNA duplex. The DNA in such an RNA:DNA duplex need notbe unmodified DNA. In certain embodiments, compounds described hereinare sufficiently “DNA-like” to elicit RNase H activity. Further, incertain embodiments, one or more non-DNA-like nucleoside in the gap of agapmer is tolerated.

In certain antisense activities, compounds described herein or a portionof the compound is loaded into an RNA-induced silencing complex (RISC),ultimately resulting in cleavage of the target nucleic acid. Forexample, certain compounds described herein result in cleavage of thetarget nucleic acid by Argonaute. Compounds that are loaded into RISCare RNAi compounds. RNAi compounds may be double-stranded (siRNA) orsingle-stranded (ssRNA).

In certain embodiments, hybridization of compounds described herein to atarget nucleic acid does not result in recruitment of a protein thatcleaves that target nucleic acid. In certain such embodiments,hybridization of the compound to the target nucleic acid results inalteration of splicing of the target nucleic acid. In certainembodiments, hybridization of the compound to a target nucleic acidresults in inhibition of a binding interaction between the targetnucleic acid and a protein or other nucleic acid. In certain suchembodiments, hybridization of the compound to a target nucleic acidresults in alteration of translation of the target nucleic acid.

Antisense activities may be observed directly or indirectly. In certainembodiments, observation or detection of an antisense activity involvesobservation or detection of a change in an amount of a target nucleicacid or protein encoded by such target nucleic acid, a change in theratio of splice variants of a nucleic acid or protein, and/or aphenotypic change in a cell or animal.

Target Nucleic Acids, Target Regions and Nucleotide Sequences

In certain embodiments, compounds described herein comprise or consistof an oligonucleotide comprising a region that is complementary to atarget nucleic acid. In certain embodiments, the target nucleic acid isan endogenous RNA molecule. In certain embodiments, the target nucleicacid encodes a protein. In certain such embodiments, the target nucleicacid is selected from: an mRNA and a pre-mRNA, including intronic,exonic and untranslated regions. In certain embodiments, the target RNAis an mRNA. In certain embodiments, the target nucleic acid is apre-mRNA. In certain such embodiments, the target region is entirelywithin an intron. In certain embodiments, the target region spans anintron/exon junction. In certain embodiments, the target region is atleast 50% within an intron.

Nucleotide sequences that encode MALAT1 include, without limitation, thefollowing: RefSEQ No. XR_001309.1 (SEQ ID NO: 1), which is incorporatedby reference in its entirety.

Hybridization

In some embodiments, hybridization occurs between a compound disclosedherein and a MALAT1 nucleic acid. The most common mechanism ofhybridization involves hydrogen bonding (e.g., Watson-Crick, Hoogsteenor reversed Hoogsteen hydrogen bonding) between complementarynucleobases of the nucleic acid molecules.

Hybridization can occur under varying conditions. Hybridizationconditions are sequence-dependent and are determined by the nature andcomposition of the nucleic acid molecules to be hybridized.

Methods of determining whether a sequence is specifically hybridizableto a target nucleic acid are well known in the art. In certainembodiments, the compounds provided herein are specifically hybridizablewith a MALAT1 nucleic acid.

Complementarity

An oligonucleotide is said to be complementary to another nucleic acidwhen the nucleobase sequence of such oligonucleotide or one or moreregions thereof matches the nucleobase sequence of anotheroligonucleotide or nucleic acid or one or more regions thereof when thetwo nucleobase sequences are aligned in opposing directions. Nucleobasematches or complementary nucleobases, as described herein, are limitedto the following pairs: adenine (A) and thymine (T), adenine (A) anduracil (U), cytosine (C) and guanine (G), and 5-methyl cytosine (mC) andguanine (G) unless otherwise specified. Complementary oligonucleotidesand/or nucleic acids need not have nucleobase complementarity at eachnucleoside and may include one or more nucleobase mismatches. Anoligonucleotide is fully complementary or 100% complementary when sucholigonucleotides have nucleobase matches at each nucleoside without anynucleobase mismatches.

In certain embodiments, compounds described herein comprise or consistof modified oligonucleotides. In certain embodiments, compoundsdescribed herein are antisense compounds. In certain embodiments,compounds comprise oligomeric compounds. Non-complementary nucleobasesbetween a compound and a MALAT1 nucleic acid may be tolerated providedthat the compound remains able to specifically hybridize to a targetnucleic acid. Moreover, a compound may hybridize over one or moresegments of a MALAT1 nucleic acid such that intervening or adjacentsegments are not involved in the hybridization event (e.g., a loopstructure, mismatch or hairpin structure).

In certain embodiments, the compounds provided herein, or a specifiedportion thereof, are, are at least, or are up to 70%, 80%, 85%, 86%,87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%complementary to a MALAT1 nucleic acid, a target region, target segment,or specified portion thereof. In certain embodiments, the compoundsprovided herein, or a specified portion thereof, are 70% to 75%, 75% to80%, 80% to 85%, 85% to 90%, 90% to 95%, 95% to 100%, or any number inbetween these ranges, complementary to a MALAT1 nucleic acid, a targetregion, target segment, or specified portion thereof. Percentcomplementarity of a compound with a target nucleic acid can bedetermined using routine methods.

For example, a compound in which 18 of 20 nucleobases of the compoundare complementary to a target region, and would therefore specificallyhybridize, would represent 90 percent complementarity. In this example,the remaining non-complementary nucleobases may be clustered orinterspersed with complementary nucleobases and need not be contiguousto each other or to complementary nucleobases. As such, a compound whichconsisting of 18 nucleobases having four non-complementary nucleobaseswhich are flanked by two regions of complete complementarity with thetarget nucleic acid would have 77.8% overall complementarity with thetarget nucleic acid. Percent complementarity of a compound with a regionof a target nucleic acid can be determined routinely using BLASTprograms (basic local alignment search tools) and PowerBLAST programsknown in the art (Altschul et al., J. Mol. Biol., 1990, 215, 403 410;Zhang and Madden, Genome Res., 1997, 7, 649 656). Percent homology,sequence identity or complementarity, can be determined by, for example,the Gap program (Wisconsin Sequence Analysis Package, Version 8 forUnix, Genetics Computer Group, University Research Park, Madison Wis.),using default settings, which uses the algorithm of Smith and Waterman(Adv. Appl. Math., 1981, 2, 482 489).

In certain embodiments, compounds described herein, or specifiedportions thereof, are fully complementary (i.e. 100% complementary) to atarget nucleic acid, or specified portion thereof. For example, acompound may be fully complementary to a MALAT1 nucleic acid, or atarget region, or a target segment or target sequence thereof. As usedherein, “fully complementary” means each nucleobase of a compound iscomplementary to the corresponding nucleobase of a target nucleic acid.For example, a 20 nucleobase compound is fully complementary to a targetsequence that is 400 nucleobases long, so long as there is acorresponding 20 nucleobase portion of the target nucleic acid that isfully complementary to the compound. Fully complementary can also beused in reference to a specified portion of the first and/or the secondnucleic acid. For example, a 20 nucleobase portion of a 30 nucleobasecompound can be “fully complementary” to a target sequence that is 400nucleobases long. The 20 nucleobase portion of the 30 nucleobasecompound is fully complementary to the target sequence if the targetsequence has a corresponding 20 nucleobase portion wherein eachnucleobase is complementary to the 20 nucleobase portion of thecompound. At the same time, the entire 30 nucleobase compound may or maynot be fully complementary to the target sequence, depending on whetherthe remaining 10 nucleobases of the compound are also complementary tothe target sequence.

In certain embodiments, compounds described herein comprise one or moremismatched nucleobases relative to the target nucleic acid. In certainsuch embodiments, antisense activity against the target is reduced bysuch mismatch, but activity against a non-target is reduced by a greateramount. Thus, in certain such embodiments selectivity of the compound isimproved. In certain embodiments, the mismatch is specificallypositioned within an oligonucleotide having a gapmer motif. In certainsuch embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6, 7, or 8from the 5′-end of the gap region. In certain such embodiments, themismatch is at position 9, 8, 7, 6, 5, 4, 3, 2, 1 from the 3′-end of thegap region. In certain such embodiments, the mismatch is at position 1,2, 3, or 4 from the 5′-end of the wing region. In certain suchembodiments, the mismatch is at position 4, 3, 2, or 1 from the 3′-endof the wing region. In certain embodiments, the mismatch is specificallypositioned within an oligonucleotide not having a gapmer motif. Incertain such embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, or 12 from the 5′-end of the oligonucleotide. Incertain such embodiments, the mismatch is at position, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, or 12 from the 3′-end of the oligonucleotide.

The location of a non-complementary nucleobase may be at the 5′ end or3′ end of the compound. Alternatively, the non-complementary nucleobaseor nucleobases may be at an internal position of the compound. When twoor more non-complementary nucleobases are present, they may becontiguous (i.e. linked) or non-contiguous. In one embodiment, anon-complementary nucleobase is located in the wing segment of a gapmeroligonucleotide.

In certain embodiments, compounds described herein that are, or are upto 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleobases in lengthcomprise no more than 4, no more than 3, no more than 2, or no more than1 non-complementary nucleobase(s) relative to a target nucleic acid,such as a MALAT1 nucleic acid, or specified portion thereof.

In certain embodiments, compounds described herein that are, or are upto 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, or 30 nucleobases in length comprise no more than 6, no morethan 5, no more than 4, no more than 3, no more than 2, or no more than1 non-complementary nucleobase(s) relative to a target nucleic acid,such as a MALAT1 nucleic acid, or specified portion thereof.

In certain embodiments, compounds described herein also include thosewhich are complementary to a portion of a target nucleic acid. As usedherein, “portion” refers to a defined number of contiguous (i.e. linked)nucleobases within a region or segment of a target nucleic acid. A“portion” can also refer to a defined number of contiguous nucleobasesof a compound. In certain embodiments, the—compounds, are complementaryto at least an 8 nucleobase portion of a target segment. In certainembodiments, the compounds are complementary to at least a 9 nucleobaseportion of a target segment. In certain embodiments, the compounds arecomplementary to at least a 10 nucleobase portion of a target segment.In certain embodiments, the compounds are complementary to at least an11 nucleobase portion of a target segment. In certain embodiments, thecompounds are complementary to at least a 12 nucleobase portion of atarget segment. In certain embodiments, the compounds are complementaryto at least a 13 nucleobase portion of a target segment.

In certain embodiments, the compounds are complementary to at least a 14nucleobase portion of a target segment. In certain embodiments, thecompounds are complementary to at least a 15 nucleobase portion of atarget segment. In certain embodiments, the compounds are complementaryto at least a 16 nucleobase portion of a target segment. Alsocontemplated are compounds that are complementary to at least a 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more nucleobase portion of atarget segment, or a range defined by any two of these values.

Identity

The compounds provided herein may also have a defined percent identityto a particular nucleotide sequence, SEQ ID NO, or compound representedby a specific ION number, or portion thereof. In certain embodiments,compounds described herein are antisense compounds or oligomericcompounds. In certain embodiments, compounds described herein aremodified oligonucleotides. As used herein, a compound is identical tothe sequence disclosed herein if it has the same nucleobase pairingability. For example, a RNA which contains uracil in place of thymidinein a disclosed DNA sequence would be considered identical to the DNAsequence since both uracil and thymidine pair with adenine. Shortenedand lengthened versions of the compounds described herein as well ascompounds having non-identical bases relative to the compounds providedherein also are contemplated. The non-identical bases may be adjacent toeach other or dispersed throughout the compound. Percent identity of ancompound is calculated according to the number of bases that haveidentical base pairing relative to the sequence to which it is beingcompared.

In certain embodiments, compounds described herein, or portions thereof,are, or are at least, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, 99% or 100% identical to one or more of the compounds orSEQ ID NOs, or a portion thereof, disclosed herein. In certainembodiments, compounds described herein are about 70%, 75%, 80%, 85%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical, or anypercentage between such values, to a particular nucleotide sequence, SEQID NO, or compound represented by a specific ION number, or portionthereof, in which the compounds comprise an oligonucleotide having oneor more mismatched nucleobases. In certain such embodiments, themismatch is at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 fromthe 5′-end of the oligonucleotide. In certain such embodiments, themismatch is at position, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 from the3′-end of the oligonucleotide.

In certain embodiments, compounds described herein comprise or consistof antisense compounds. In certain embodiments, a portion of theantisense compound is compared to an equal length portion of the targetnucleic acid. In certain embodiments, an 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portion is comparedto an equal length portion of the target nucleic acid.

In certain embodiments, compounds described herein comprise or consistof oligonucleotides. In certain embodiments, a portion of theoligonucleotide is compared to an equal length portion of the targetnucleic acid. In certain embodiments, an 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portion is comparedto an equal length portion of the target nucleic acid.

Certain Modified Compounds

In certain embodiments, compounds described herein comprise or consistof oligonucleotides consisting of linked nucleosides. Oligonucleotidesmay be unmodified oligonucleotides (RNA or DNA) or may be modifiedoligonucleotides. Modified oligonucleotides comprise at least onemodification relative to unmodified RNA or DNA (i.e., comprise at leastone modified nucleoside (comprising a modified sugar moiety and/or amodified nucleobase) and/or at least one modified internucleosidelinkage).

A. Modified Nucleosides

Modified nucleosides comprise a modified sugar moiety or a modifiednucleobase or both a modified sugar moiety and a modified nucleobase.

1. Modified Sugar Moieties

In certain embodiments, sugar moieties are non-bicyclic modified sugarmoieties. In certain embodiments, modified sugar moieties are bicyclicor tricyclic sugar moieties. In certain embodiments, modified sugarmoieties are sugar surrogates. Such sugar surrogates may comprise one ormore substitutions corresponding to those of other types of modifiedsugar moieties.

In certain embodiments, modified sugar moieties are non-bicyclicmodified sugar moieties comprising a furanosyl ring with one or moreacyclic substituent, including but not limited to substituents at the2′, 4′, and/or 5′ positions. In certain embodiments one or more acyclicsubstituent of non-bicyclic modified sugar moieties is branched.Examples of 2′-substituent groups suitable for non-bicyclic modifiedsugar moieties include but are not limited to: 2′-F, 2′-OCH₃ (“OMe” or“O-methyl”), and 2′-O(CH₂)₂OCH₃ (“MOE”). In certain embodiments,2′-substituent groups are selected from among: halo, allyl, amino,azido, SH, CN, OCN, CF₃, OCF₃, O—C₁-C₁₀ alkoxy, O—C₁-C₁₀ substitutedalkoxy, O—C₁-C₁₀ alkyl, O—C₁-C₁₀ substituted alkyl, S-alkyl,N(R_(m))-alkyl, O-alkenyl, S-alkenyl, N(R_(m))-alkenyl, O-alkynyl,S-alkynyl, N(R_(m))-alkynyl, O-alkylenyl-O-alkyl, alkynyl, alkaryl,aralkyl, O-alkaryl, O-aralkyl, O(CH₂)₂SCH₃, O(CH₂)₂ON(R_(m))(R_(n)) orOCH₂C(═O)—N(R_(m))(R_(n)), where each R_(m) and R_(n) is, independently,H, an amino protecting group, or substituted or unsubstituted C₁-C₁₀alkyl, and the 2′-substituent groups described in Cook et al., U.S. Pat.No. 6,531,584; Cook et al., U.S. Pat. No. 5,859,221; and Cook et al.,U.S. Pat. No. 6,005,087. Certain embodiments of these 2′-substituentgroups can be further substituted with one or more substituent groupsindependently selected from among: hydroxyl, amino, alkoxy, carboxy,benzyl, phenyl, nitro (NO₂), thiol, thioalkoxy, thioalkyl, halogen,alkyl, aryl, alkenyl and alkynyl. Examples of 4′-substituent groupssuitable for linearly non-bicyclic modified sugar moieties include butare not limited to alkoxy (e.g., methoxy), alkyl, and those described inManoharan et al., WO 2015/106128. Examples of 5′-substituent groupssuitable for non-bicyclic modified sugar moieties include but are notlimited to: 5′-methyl (R or S), 5′-vinyl, and 5′-methoxy. In certainembodiments, non-bicyclic modified sugars comprise more than onenon-bridging sugar substituent, for example, 2′-F-5′-methyl sugarmoieties and the modified sugar moieties and modified nucleosidesdescribed in Migawa et al., US2010/190837 and Rajeev et al.,US2013/0203836.

In certain embodiments, a 2′-substituted nucleoside or 2′-non-bicyclicmodified nucleoside comprises a sugar moiety comprising a linear2′-substituent group selected from: F, NH₂, N₃, OCF₃, OCH₃, O(CH₂)₃NH₂,CH₂CH═CH₂, OCH₂CH═CH₂, OCH₂CH₂OCH₃, O(CH₂)₂SCH₃,O(CH₂)₂ON(R_(m))(R_(n)), O(CH₂)₂O(CH₂)₂N(CH₃)₂, and N-substitutedacetamide (OCH₂C(═O)—N(R_(m))(R_(n))), where each R_(m) and R_(n) is,independently, H, an amino protecting group, or substituted orunsubstituted C₁-C₁₀ alkyl.

In certain embodiments, a 2′-substituted nucleoside or 2′-non-bicyclicmodified nucleoside comprises a sugar moiety comprising a linear2′-substituent group selected from: F, OCF₃, OCH₃, OCH₂CH₂OCH₃,O(CH₂)₂SCH₃, O(CH₂)₂ON(CH₃)₂, O(CH₂)₂O(CH₂)₂N(CH₃)₂, andOCH₂C(═O)—N(H)CH₃ (“NMA”).

In certain embodiments, a 2′-substituted nucleoside or 2′-non-bicyclicmodified nucleoside comprises a sugar moiety comprising a linear2′-substituent group selected from: F, OCH₃, and OCH₂CH₂OCH₃.

Nucleosides comprising modified sugar moieties, such as non-bicyclicmodified sugar moieties, are referred to by the position(s) of thesubstitution(s) on the sugar moiety of the nucleoside. For example,nucleosides comprising 2′-substituted or 2-modified sugar moieties arereferred to as 2′-substituted nucleosides or 2-modified nucleosides.

Certain modified sugar moieties comprise a bridging sugar substituentthat forms a second ring resulting in a bicyclic sugar moiety. Incertain such embodiments, the bicyclic sugar moiety comprises a bridgebetween the 4′ and the 2′ furanose ring atoms. Examples of such 4′ to 2′bridging sugar substituents include but are not limited to: 4′-CH₂-2′,4′-(CH₂)₂-2′, 4′-(CH₂)₃-2′, 4′-CH₂—O-2′ (“LNA”), 4′-CH₂—S-2′,4′-(CH₂)₂—O-2′ (“ENA”), 4′-CH(CH₃)—O-2′ (referred to as “constrainedethyl” or “cEt” when in the S configuration), 4′-CH₂—O—CH₂-2′,4′-CH₂—N(R)-2′, 4′-CH(CH₂OCH₃)—O-2′ (“constrained MOE” or “cMOE”) andanalogs thereof (see, e.g., Seth et al., U.S. Pat. No. 7,399,845, Bhatet al., U.S. Pat. No. 7,569,686, Swayze et al., U.S. Pat. No. 7,741,457,and Swayze et al., U.S. Pat. No. 8,022,193), 4′-C(CH₃)(CH₃)—O-2′ andanalogs thereof (see, e.g., Seth et al., U.S. Pat. No. 8,278,283),4′-CH₂—N(OCH₃)-2′ and analogs thereof (see, e.g., Prakash et al., U.S.Pat. No. 8,278,425), 4′-CH₂—O—N(CH₃)-2′ (see, e.g., Allerson et al.,U.S. Pat. No. 7,696,345 and Allerson et al., U.S. Pat. No. 8,124,745),4′-CH₂—C(H)(CH₃)-2′ (see, e.g., Zhou, et al., J. Org. Chem., 2009, 74,118-134), 4′-CH₂—C(═CH₂)-2′ and analogs thereof (see e.g., Seth et al.,U.S. Pat. No. 8,278,426), 4′-C(R_(a)R_(b))—N(R)—O-2′,4′-C(R_(a)R_(b))—O—N(R)-2′, 4′-CH₂—O—N(R)-2′, and 4′-CH₂—N(R)—O-2′,wherein each R, R_(a), and R_(b) is, independently, H, a protectinggroup, or C₁-C₁₂ alkyl (see, e.g. Imanishi et al., U.S. Pat. No.7,427,672).

In certain embodiments, such 4′ to 2′ bridges independently comprisefrom 1 to 4 linked groups independently selected from:—[C(R_(a))(R_(b))]_(n)—, —[C(R_(a))(R_(b))]_(n)—O—, —C(R_(a))═C(R_(b))—,—C(R_(a))═N—, —C(═NR_(a))—, —C(═O)—, —C(═S)—, —O—, —Si(R_(a))₂—,—S(═O)_(n)—, and —N(R_(a))—;

wherein:

x is 0, 1, or 2;

n is 1, 2, 3, or 4;

each R_(a) and R_(b) is, independently, H, a protecting group, hydroxyl,C₁-C₁₂ alkyl, substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, substitutedC₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, substituted C₂-C₁₂ alkynyl, C₅-C₂₀ aryl,substituted C₅-C₂₀ aryl, heterocycle radical, substituted heterocycleradical, heteroaryl, substituted heteroaryl, C₅-C₇ alicyclic radical,substituted C₅-C₇ alicyclic radical, halogen, OJ₁, NJ₁J₂, SJ₁, N₃,COOJ₁, acyl (C(═O)—H), substituted acyl, CN, sulfonyl (S(═O)₂-J₁), orsulfoxyl (S(═O)-J₁); and each J₁ and J₂ is, independently, H, C₁-C₁₂alkyl, substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, substituted C₂-C₁₂alkenyl, C₂-C₁₂ alkynyl, substituted C₂-C₁₂ alkynyl, C₅-C₂₀ aryl,substituted C₅-C₂₀ aryl, acyl (C(═O)—H), substituted acyl, a heterocycleradical, a substituted heterocycle radical, C₁-C₁₂ aminoalkyl,substituted C₁-C₁₂ aminoalkyl, or a protecting group.

Additional bicyclic sugar moieties are known in the art, see, forexample: Freier et al., Nucleic Acids Research, 1997, 25(22), 4429-4443,Albaek et al., J. Org. Chem., 2006, 71, 7731-7740, Singh et al., Chem.Commun., 1998, 4, 455-456; Koshkin et al., Tetrahedron, 1998, 54,3607-3630; Wahlestedt et al., Proc. Natl. Acad. Sci. U S. A., 2000, 97,5633-5638; Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222;Singh et al., J. Org. Chem., 1998, 63, 10035-10039; Srivastava et al.,J. Am. Chem. Soc., 2007, 129, 8362-8379; Elayadi et al., Curr. OpinionInvens. Drugs, 2001, 2, 558-561; Braasch et al., Chem. Biol., 2001, 8,1-7; Orum et al., Curr. Opinion Mol. Ther., 2001, 3, 239-243; Wengel etal., U.S. Pat. No. 7,053,207, Imanishi et al., U.S. Pat. No. 6,268,490,Imanishi et al. U.S. Pat. No. 6,770,748, Imanishi et al., U.S. RE44,779;Wengel et al., U.S. Pat. No. 6,794,499, Wengel et al., U.S. Pat. No.6,670,461; Wengel et al., U.S. Pat. No. 7,034,133, Wengel et al., U.S.Pat. No. 8,080,644; Wengel et al., U.S. Pat. No. 8,034,909; Wengel etal., U.S. Pat. No. 8,153,365; Wengel et al., U.S. Pat. No. 7,572,582;and Ramasamy et al., U.S. Pat. No. 6,525,191, Torsten et al., WO2004/106356, Wengel et al., WO 1999/014226; Seth et al., WO 2007/134181;Seth et al., U.S. Pat. No. 7,547,684; Seth et al., U.S. Pat. No.7,666,854; Seth et al., U.S. Pat. No. 8,088,746; Seth et al., U.S. Pat.No. 7,750,131; Seth et al., U.S. Pat. No. 8,030,467; Seth et al., U.S.Pat. No. 8,268,980; Seth et al., U.S. Pat. No. 8,546,556; Seth et al.,U.S. Pat. No. 8,530,640; Migawa et al., U.S. Pat. No. 9,012,421; Seth etal., U.S. Pat. No. 8,501,805; Allerson et al., US2008/0039618; andMigawa et al., US2015/0191727.

In certain embodiments, bicyclic sugar moieties and nucleosidesincorporating such bicyclic sugar moieties are further defined byisomeric configuration. For example, an LNA nucleoside (describedherein) may be in the α-L configuration or in the β-D configuration.

α-L-methyleneoxy (4′-CH₂—O-2′) or α-L-LNA bicyclic nucleosides have beenincorporated into oligonucleotides that showed antisense activity(Frieden et al., Nucleic Acids Research, 2003, 21, 6365-6372). Herein,general descriptions of bicyclic nucleosides include both isomericconfigurations. When the positions of specific bicyclic nucleosides(e.g., LNA or cEt) are identified in exemplified embodiments herein,they are in the β-D configuration, unless otherwise specified.

In certain embodiments, modified sugar moieties comprise one or morenon-bridging sugar substituent and one or more bridging sugarsubstituent (e.g., 5′-substituted and 4′-2′ bridged sugars).

In certain embodiments, modified sugar moieties are sugar surrogates. Incertain such embodiments, the oxygen atom of the sugar moiety isreplaced, e.g., with a sulfur, carbon or nitrogen atom. In certain suchembodiments, such modified sugar moieties also comprise bridging and/ornon-bridging substituents as described herein. For example, certainsugar surrogates comprise a 4′-sulfur atom and a substitution at the2′-position (see, e.g., Bhat et al., U.S. Pat. No. 7,875,733 and Bhat etal., U.S. Pat. No. 7,939,677) and/or the 5′ position.

In certain embodiments, sugar surrogates comprise rings having otherthan 5 atoms. For example, in certain embodiments, a sugar surrogatecomprises a six-membered tetrahydropyran (“THP”). Such tetrahydropyransmay be further modified or substituted. Nucleosides comprising suchmodified tetrahydropyrans include but are not limited to hexitol nucleicacid (“HNA”), anitol nucleic acid (“ANA”), manitol nucleic acid (“MNA”)(see e.g., Leumann, C J. Bioorg. & Med. Chem. 2002, 10, 841-854), fluoroHNA:

(“F-HNA”, see e.g., Swayze et al., U.S. Pat. No. 8,088,904; Swayze etal., U.S. Pat. No. 8,440,803; and Swayze et al., U.S. Pat. No.9,005,906, F-HNA can also be referred to as a F-THP or 3′-fluorotetrahydropyran), and nucleosides comprising additional modified THPcompounds having the formula:

wherein, independently, for each of said modified THP nucleoside:

Bx is a nucleobase moiety;

T₃ and T₄ are each, independently, an internucleoside linking grouplinking the modified THP nucleoside to the remainder of anoligonucleotide or one of T₃ and T₄ is an internucleoside linking grouplinking the modified THP nucleoside to the remainder of anoligonucleotide and the other of T₃ and T₄ is H, a hydroxyl protectinggroup, a linked conjugate group, or a 5′ or 3′-terminal group; q₁, q₂,q₃, q₄, q₅, q₆ and q₇ are each, independently, H, C₁-C₆ alkyl,substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆alkynyl, or substituted C₂-C₆ alkynyl; and each of R₁ and R₂ isindependently selected from among: hydrogen, halogen, substituted orunsubstituted alkoxy, NJ₁J₂, SJ₁, N₃, OC(═X)J₁, OC(═X)NJ₁J₂,NJ₃C(═X)NJ₁J₂, and CN, wherein X is O, S or NJ₁, and each J₁, J₂, and J₃is, independently, H or C₁-C₆ alkyl.

In certain embodiments, modified THP nucleosides are provided whereinq₁, q₂, q₃, q₄, q₅, q₆ and q₇ are each H. In certain embodiments, atleast one of q₁, q₂, q₃, q₄, q₅, q₆ and q₇ is other than H. In certainembodiments, at least one of q₁, q₂, q₃, q₄, q₅, q₆ and q₇ is methyl. Incertain embodiments, modified THP nucleosides are provided wherein oneof R₁ and R₂ is F. In certain embodiments, R₁ is F and R₂ is H, incertain embodiments, R₁ is methoxy and R₂ is H, and in certainembodiments, R₁ is methoxyethoxy and R₂ is H.

In certain embodiments, sugar surrogates comprise rings having more than5 atoms and more than one heteroatom. For example, nucleosidescomprising morpholino sugar moieties and their use in oligonucleotideshave been reported (see, e.g., Braasch et al., Biochemistry, 2002, 41,4503-4510 and Summerton et al., U.S. Pat. No. 5,698,685; Summerton etal., U.S. Pat. No. 5,166,315; Summerton et al., U.S. Pat. No. 5,185,444;and Summerton et al., U.S. Pat. No. 5,034,506). As used here, the term“morpholino” means a sugar surrogate having the following structure:

In certain embodiments, morpholinos may be modified, for example byadding or altering various substituent groups from the above morpholinostructure. Such sugar surrogates are referred to herein as “modifiedmorpholinos.”

In certain embodiments, sugar surrogates comprise acyclic moieties.Examples of nucleosides and oligonucleotides comprising such acyclicsugar surrogates include but are not limited to: peptide nucleic acid(“PNA”), acyclic butyl nucleic acid (see, e.g., Kumar et al., Org.Biomol. Chem., 2013, 11, 5853-5865), and nucleosides andoligonucleotides described in Manoharan et al., US2013/130378.

Many other bicyclic and tricyclic sugar and sugar surrogate ring systemsare known in the art that can be used in modified nucleosides.

2. Modified Nucleobases

Nucleobase (or base) modifications or substitutions are structurallydistinguishable from, yet functionally interchangeable with, naturallyoccurring or synthetic unmodified nucleobases. Both natural and modifiednucleobases are capable of participating in hydrogen bonding. Suchnucleobase modifications can impart nuclease stability, binding affinityor some other beneficial biological property to antisense compounds.

In certain embodiments, compounds described herein comprise modifiedoligonucleotides. In certain embodiments, modified oligonucleotidescomprise one or more nucleoside comprising an unmodified nucleobase. Incertain embodiments, modified oligonucleotides comprise one or morenucleoside comprising a modified nucleobase. In certain embodiments,modified oligonucleotides comprise one or more nucleoside that does notcomprise a nucleobase, referred to as an abasic nucleoside.

In certain embodiments, modified nucleobases are selected from:5-substituted pyrimidines, 6-azapyrimi¬dines, alkyl or alkynylsubstituted pyrimidines, alkyl substituted purines, and N-2, N-6 and 0-6substituted purines. In certain embodiments, modified nucleobases areselected from: 2-aminopropyladenine, 5-hydroxymethyl cytosine,5-methylcytosine, xanthine, hypoxanthine, 2-aminoadenine,6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil,2-thiothymine and 2-thiocytosine, 5-propynyl (C═C—CH₃) uracil,5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine,5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol,8-thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo,particularly 5-bromo, 5-trifluoromethyl, 5-halouracil, and5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine,2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine,3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine,4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine,5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases,promiscuous bases, size-expanded bases, and fluorinated bases. Furthermodified nucleobases include tricyclic pyrimidines, such as1,3-diazaphenoxazine-2-one, 1,3-diazaphenothiazine-2-one and9-(2-aminoethoxy)-1,3-diazaphenoxazine-2-one (G-clamp). Modifiednucleobases may also include those in which the purine or pyrimidinebase is replaced with other heterocycles, for example 7-deaza-adenine,7-deazaguanosine, 2-aminopyridine and 2-pyridone. Further nucleobasesinclude those disclosed in Merigan et al., U.S. Pat. No. 3,687,808,those disclosed in The Concise Encyclopedia Of Polymer Science AndEngineering, Kroschwitz, J. I., Ed., John Wiley & Sons, 1990, 858-859;Englisch et al., Angewandte Chemie, International Edition, 1991, 30,613; Sanghvi, Y. S., Chapter 15, Antisense Research and Applications,Crooke, S. T. and Lebleu, B., Eds., CRC Press, 1993, 273-288; and thosedisclosed in Chapters 6 and 15, Antisense Drug Technology, Crooke S. T.,Ed., CRC Press, 2008, 163-166 and 442-443.

Publications that teach the preparation of certain of the above notedmodified nucleobases as well as other modified nucleobases includewithout limitation, Manoharan et al., US2003/0158403, Manoharan et al.,US2003/0175906; Dinh et al., U.S. Pat. No. 4,845,205; Spielvogel et al.,U.S. Pat. No. 5,130,302; Rogers et al., U.S. Pat. No. 5,134,066;Bischofberger et al., U.S. Pat. No. 5,175,273; Urdea et al., U.S. Pat.No. 5,367,066; Benner et al., U.S. Pat. No. 5,432,272; Matteucci et al.,U.S. Pat. No. 5,434,257; Gmeiner et al., U.S. Pat. No. 5,457,187; Cooket al., U.S. Pat. No. 5,459,255; Froehler et al., U.S. Pat. No.5,484,908; Matteucci et al., U.S. Pat. No. 5,502,177; Hawkins et al.,U.S. Pat. No. 5,525,711; Haralambidis et al., U.S. Pat. No. 5,552,540;Cook et al., U.S. Pat. No. 5,587,469; Froehler et al., U.S. Pat. No.5,594,121; Switzer et al., U.S. Pat. No. 5,596,091; Cook et al., U.S.Pat. No. 5,614,617; Froehler et al., U.S. Pat. No. 5,645,985; Cook etal., U.S. Pat. No. 5,681,941; Cook et al., U.S. Pat. No. 5,811,534; Cooket al., U.S. Pat. No. 5,750,692; Cook et al., U.S. Pat. No. 5,948,903;Cook et al., U.S. Pat. No. 5,587,470; Cook et al., U.S. Pat. No.5,457,191; Matteucci et al., U.S. Pat. No. 5,763,588; Froehler et al.,U.S. Pat. No. 5,830,653; Cook et al., U.S. Pat. No. 5,808,027; Cook etal., U.S. Pat. No. 6,166,199; and Matteucci et al., U.S. Pat. No.6,005,096.

In certain embodiments, compounds targeted to a MALAT1 nucleic acidcomprise one or more modified nucleobases. In certain embodiments, themodified nucleobase is 5-methylcytosine. In certain embodiments, eachcytosine is a 5-methylcytosine.

3. Modified Internucleoside Linkages

The naturally occurring internucleoside linkage of RNA and DNA is a 3′to 5′ phosphodiester linkage In certain embodiments, compounds describedherein having one or more modified, i.e. non-naturally occurring,internucleoside linkages are often selected over compounds havingnaturally occurring internucleoside linkages because of desirableproperties such as, for example, enhanced cellular uptake, enhancedaffinity for target nucleic acids, and increased stability in thepresence of nucleases.

Representative internucleoside linkages having a chiral center includebut are not limited to alkylphosphonates and phosphorothioates. Modifiedoligonucleotides comprising internucleoside linkages having a chiralcenter can be prepared as populations of modified oligonucleotidescomprising stereorandom internucleoside linkages, or as populations ofmodified oligonucleotides comprising phosphorothioate linkages inparticular stereochemical configurations. In certain embodiments,populations of modified oligonucleotides comprise phosphorothioateinternucleoside linkages wherein all of the phosphorothioateinternucleoside linkages are stereorandom. Such modifiedoligonucleotides can be generated using synthetic methods that result inrandom selection of the stereochemical configuration of eachphosphorothioate linkage. Nonetheless, as is well understood by those ofskill in the art, each individual phosphorothioate of each individualoligonucleotide molecule has a defined stereoconfiguration. In certainembodiments, populations of modified oligonucleotides are enriched formodified oligonucleotides comprising one or more particularphosphorothioate internucleoside linkages in a particular, independentlyselected stereochemical configuration. In certain embodiments, theparticular configuration of the particular phosphorothioate linkage ispresent in at least 65% of the molecules in the population. In certainembodiments, the particular configuration of the particularphosphorothioate linkage is present in at least 70% of the molecules inthe population. In certain embodiments, the particular configuration ofthe particular phosphorothioate linkage is present in at least 80% ofthe molecules in the population. In certain embodiments, the particularconfiguration of the particular phosphorothioate linkage is present inat least 90% of the molecules in the population. In certain embodiments,the particular configuration of the particular phosphorothioate linkageis present in at least 99% of the molecules in the population. Suchchirally enriched populations of modified oligonucleotides can begenerated using synthetic methods known in the art, e.g., methodsdescribed in Oka et al., JACS 125, 8307 (2003), Wan et al. Nuc. Acid.Res. 42, 13456 (2014), and WO 2017/015555. In certain embodiments, apopulation of modified oligonucleotides is enriched for modifiedoligonucleotides having at least one indicated phosphorothioate in the(Sp) configuration. In certain embodiments, a population of modifiedoligonucleotides is enriched for modified oligonucleotides having atleast one phosphorothioate in the (Rp) configuration. In certainembodiments, modified oligonucleotides comprising (Rp) and/or (Sp)phosphorothioates comprise one or more of the following formulas,respectively, wherein “B” indicates a nucleobase:

Unless otherwise indicated, chiral internucleoside linkages of modifiedoligonucleotides described herein can be stereorandom or in a particularstereochemical configuration.

In certain embodiments, compounds targeted to an MALAT1 nucleic acidcomprise one or more modified internucleoside linkages. In certainembodiments, the modified internucleoside linkages are phosphorothioatelinkages. In certain embodiments, each internucleoside linkage of anantisense compound is a phosphorothioate internucleoside linkage.

In certain embodiments, compounds described herein compriseoligonucleotides. Oligonucleotides having modified internucleosidelinkages include internucleoside linkages that retain a phosphorus atomas well as internucleoside linkages that do not have a phosphorus atom.Representative phosphorus containing internucleoside linkages include,but are not limited to, phosphodiesters, phosphotriesters,methylphosphonates, phosphoramidate, and phosphorothioates. Methods ofpreparation of phosphorous-containing and non-phosphorous-containinglinkages are well known.

In certain embodiments, nucleosides of modified oligonucleotides may belinked together using any internucleoside linkage. The two main classesof internucleoside linking groups are defined by the presence or absenceof a phosphorus atom. Representative phosphorus-containinginternucleoside linkages include but are not limited to phosphates,which contain a phosphodiester bond (“P═O”) (also referred to asunmodified or naturally occurring linkages), phosphotriesters,methylphosphonates, phosphoramidates, and phosphorothioates (“P═S”), andphosphorodithioates (“HS—P═S”). Representative non-phosphorus containinginternucleoside linking groups include but are not limited tomethylenemethylimino (—CH2-N(CH3)-O—CH2-), thiodiester, thionocarbamate(—O—C(═O)(NH)—S—); siloxane (—O—SiH2-O—); and N,N′-dimethylhydrazine(—CH2-N(CH3)-N(CH3)-). Modified internucleoside linkages, compared tonaturally occurring phosphate linkages, can be used to alter, typicallyincrease, nuclease resistance of the oligonucleotide. In certainembodiments, internucleoside linkages having a chiral atom can beprepared as a racemic mixture, or as separate enantiomers.Representative chiral internucleoside linkages include but are notlimited to alkylphosphonates and phosphorothioates. Methods ofpreparation of phosphorous-containing and non-phosphorous-containinginternucleoside linkages are well known to those skilled in the art.

Neutral internucleoside linkages include, without limitation,phosphotriesters, methylphosphonates, MMI (3′-CH2-N(CH3)-O-5′), amide-3(3′-CH2-C(═O)—N(H)-5′), amide-4 (3′-CH2-N(H)—C(═O)-5′), formacetal(3′-O—CH2-O-5′), methoxypropyl, and thioformacetal (3′-S—CH2-O-5′).Further neutral internucleoside linkages include nonionic linkagescomprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide,sulfide, sulfonate ester and amides (See for example: CarbohydrateModifications in Antisense Research; Y. S. Sanghvi and P. D. Cook, Eds.,ACS Symposium Series 580; Chapters 3 and 4, 40-65). Further neutralinternucleoside linkages include nonionic linkages comprising mixed N,O, S and CH₂ component parts.

In certain embodiments, oligonucleotides comprise modifiedinternucleoside linkages arranged along the oligonucleotide or regionthereof in a defined pattern or modified internucleoside linkage motif.In certain embodiments, internucleoside linkages are arranged in agapped motif. In such embodiments, the internucleoside linkages in eachof two wing regions are different from the internucleoside linkages inthe gap region. In certain embodiments the internucleoside linkages inthe wings are phosphodiester and the internucleoside linkages in the gapare phosphorothioate. The nucleoside motif is independently selected, sosuch oligonucleotides having a gapped internucleoside linkage motif mayor may not have a gapped nucleoside motif and if it does have a gappednucleoside motif, the wing and gap lengths may or may not be the same.

In certain embodiments, oligonucleotides comprise a region having analternating internucleoside linkage motif. In certain embodiments,oligonucleotides comprise a region of uniformly modified internucleosidelinkages. In certain such embodiments, the oligonucleotide comprises aregion that is uniformly linked by phosphorothioate internucleosidelinkages. In certain embodiments, the oligonucleotide is uniformlylinked by phosphorothioate. In certain embodiments, each internucleosidelinkage of the oligonucleotide is selected from phosphodiester andphosphorothioate. In certain embodiments, each internucleoside linkageof the oligonucleotide is selected from phosphodiester andphosphorothioate and at least one internucleoside linkage isphosphorothioate.

In certain embodiments, the oligonucleotide comprises at least 6phosphorothioate internucleoside linkages. In certain embodiments, theoligonucleotide comprises at least 8 phosphorothioate internucleosidelinkages. In certain embodiments, the oligonucleotide comprises at least10 phosphorothioate internucleoside linkages. In certain embodiments,the oligonucleotide comprises at least one block of at least 6consecutive phosphorothioate internucleoside linkages. In certainembodiments, the oligonucleotide comprises at least one block of atleast 8 consecutive phosphorothioate internucleoside linkages. Incertain embodiments, the oligonucleotide comprises at least one block ofat least 10 consecutive phosphorothioate internucleoside linkages. Incertain embodiments, the oligonucleotide comprises at least block of atleast one 12 consecutive phosphorothioate internucleoside linkages. Incertain such embodiments, at least one such block is located at the 3′end of the oligonucleotide. In certain such embodiments, at least onesuch block is located within 3 nucleosides of the 3′ end of theoligonucleotide.

In certain embodiments, oligonucleotides comprise one or moremethylphosponate linkages. In certain embodiments, oligonucleotideshaving a gapmer nucleoside motif comprise a linkage motif comprising allphosphorothioate linkages except for one or two methylphosponatelinkages. In certain embodiments, one methylphosponate linkage is in thecentral gap of an oligonucleotide having a gapmer nucleoside motif.

In certain embodiments, it is desirable to arrange the number ofphosphorothioate internucleoside linkages and phosphodiesterinternucleoside linkages to maintain nuclease resistance. In certainembodiments, it is desirable to arrange the number and position ofphosphorothioate internucleoside linkages and the number and position ofphosphodiester internucleoside linkages to maintain nuclease resistance.In certain embodiments, the number of phosphorothioate internucleosidelinkages may be decreased and the number of phosphodiesterinternucleoside linkages may be increased. In certain embodiments, thenumber of phosphorothioate internucleoside linkages may be decreased andthe number of phosphodiester internucleoside linkages may be increasedwhile still maintaining nuclease resistance. In certain embodiments itis desirable to decrease the number of phosphorothioate internucleosidelinkages while retaining nuclease resistance. In certain embodiments itis desirable to increase the number of phosphodiester internucleosidelinkages while retaining nuclease resistance.

Certain Motifs

In certain embodiments, compounds described herein compriseoligonucleotides. Oligonucleotides can have a motif, e.g. a pattern ofunmodified and/or modified sugar moieties, nucleobases, and/orinternucleoside linkages. In certain embodiments, modifiedoligonucleotides comprise one or more modified nucleoside comprising amodified sugar. In certain embodiments, modified oligonucleotidescomprise one or more modified nucleosides comprising a modifiednucleobase. In certain embodiments, modified oligonucleotides compriseone or more modified internucleoside linkage. In such embodiments, themodified, unmodified, and differently modified sugar moieties,nucleobases, and/or internucleoside linkages of a modifiedoligonucleotide define a pattern or motif. In certain embodiments, thepatterns of sugar moieties, nucleobases, and internucleoside linkagesare each independent of one another. Thus, a modified oligonucleotidemay be described by its sugar motif, nucleobase motif and/orinternucleoside linkage motif (as used herein, nucleobase motifdescribes the modifications to the nucleobases independent of thesequence of nucleobases).

a. Certain Sugar Motifs

In certain embodiments, compounds described herein compriseoligonucleotides. In certain embodiments, oligonucleotides comprise oneor more type of modified sugar and/or unmodified sugar moiety arrangedalong the oligonucleotide or region thereof in a defined pattern orsugar motif. In certain instances, such sugar motifs include but are notlimited to any of the sugar modifications discussed herein.

In certain embodiments, modified oligonucleotides comprise or consist ofa region having a gapmer motif, which comprises two external regions or“wings” and a central or internal region or “gap.” The three regions ofa gapmer motif (the 5′-wing, the gap, and the 3′-wing) form a contiguoussequence of nucleosides wherein at least some of the sugar moieties ofthe nucleosides of each of the wings differ from at least some of thesugar moieties of the nucleosides of the gap. Specifically, at least thesugar moieties of the nucleosides of each wing that are closest to thegap (the 3′-most nucleoside of the 5′-wing and the 5′-most nucleoside ofthe 3′-wing) differ from the sugar moiety of the neighboring gapnucleosides, thus defining the boundary between the wings and the gap(i.e., the wing/gap junction). In certain embodiments, the sugarmoieties within the gap are the same as one another. In certainembodiments, the gap includes one or more nucleoside having a sugarmoiety that differs from the sugar moiety of one or more othernucleosides of the gap. In certain embodiments, the sugar motifs of thetwo wings are the same as one another (symmetric gapmer). In certainembodiments, the sugar motif of the 5′-wing differs from the sugar motifof the 3′-wing (asymmetric gapmer).

In certain embodiments, the wings of a gapmer comprise 1-5 nucleosides.In certain embodiments, the wings of a gapmer comprise 2-5 nucleosides.In certain embodiments, the wings of a gapmer comprise 3-5 nucleosides.In certain embodiments, the nucleosides of a gapmer are all modifiednucleosides.

In certain embodiments, the gap of a gapmer comprises 7-12 nucleosides.In certain embodiments, the gap of a gapmer comprises 7-10 nucleosides.In certain embodiments, the gap of a gapmer comprises 8-10 nucleosides.In certain embodiments, the gap of a gapmer comprises 10 nucleosides. Incertain embodiment, each nucleoside of the gap of a gapmer is anunmodified 2′-deoxy nucleoside.

In certain embodiments, the gapmer is a deoxy gapmer. In suchembodiments, the nucleosides on the gap side of each wing/gap junctionare unmodified 2′-deoxy nucleosides and the nucleosides on the wingsides of each wing/gap junction are modified nucleosides. In certainsuch embodiments, each nucleoside of the gap is an unmodified 2′-deoxynucleoside. In certain such embodiments, each nucleoside of each wing isa modified nucleoside.

In certain embodiments, a modified oligonucleotide has a fully modifiedsugar motif wherein each nucleoside of the modified oligonucleotidecomprises a modified sugar moiety. In certain embodiments, modifiedoligonucleotides comprise or consist of a region having a fully modifiedsugar motif wherein each nucleoside of the region comprises a modifiedsugar moiety. In certain embodiments, modified oligonucleotides compriseor consist of a region having a fully modified sugar motif, wherein eachnucleoside within the fully modified region comprises the same modifiedsugar moiety, referred to herein as a uniformly modified sugar motif. Incertain embodiments, a fully modified oligonucleotide is a uniformlymodified oligonucleotide. In certain embodiments, each nucleoside of auniformly modified comprises the same 2′-modification.

In certain embodiments, a modified oligonucleotide can comprise a sugarmotif described in Swayze et al., US2010/0197762; Freier et al.,US2014/0107330; Freier et al., US2015/0184153; and Seth et al.,US2015/0267195, each of which is incorporated by reference in itsentirety herein.

Certain embodiments provided herein are directed to modified oligomericcompounds useful for inhibiting target nucleic acid expression, whichcan be useful for treating, preventing, ameliorating, or slowingprogression of a disease associated with such a target nucleic acid. Incertain embodiments, the modified oligomeric compounds compriseantisense oligonucleotides that are gapmers having certain sugar motifs.In certain embodiments, the gapmer sugar motifs provided herein can becombined with any nucleobase sequence and any internucleoside linkagemotif to form potent antisense oligonucleotides.

In certain embodiments, a method comprises contacting a cell oradministering to a subject a compound comprising a modifiedoligonucleotide consisting of 16 linked nucleosides and having themotif: ekk-d9-kkee, wherein ‘d’ represents a 2′-deoxyribose sugar, ‘k’represents a cEt nucleoside, and ‘e’ represents a 2′-MOE nucleoside. Incertain embodiments, the cell is a cancer cell. In certain embodiments,the subject has cancer. In certain embodiments, administering thecompound to the subject treats the subject's cancer.

In certain embodiments, a method comprises contacting a cell oradministering to a subject a compound comprising a modifiedoligonucleotide consisting of 16 linked nucleosides and having themotif: k-d9-kekeke, wherein ‘d’ represents a 2′-deoxyribose sugar, ‘k’represents a cEt nucleoside, and ‘e’ represents a 2′-MOE nucleoside. Incertain embodiments, the cell is a cancer cell. In certain embodiments,the subject has cancer. In certain embodiments, administering thecompound to the subject treats the subject's cancer.

In certain embodiments, a method comprises contacting a cell oradministering to a subject a compound comprising a modifiedoligonucleotide consisting of 16 linked nucleosides and having themotif: kkk-d8-kekek, wherein ‘d’ represents a 2′-deoxyribose sugar, ‘k’represents a cEt nucleoside, and ‘e’ represents a 2′-MOE nucleoside. Incertain embodiments, the cell is a cancer cell. In certain embodiments,the subject has cancer. In certain embodiments, administering thecompound to the subject treats the subject's cancer.

In certain embodiments, a method comprises contacting a cell oradministering to a subject a compound comprising a modifiedoligonucleotide consisting of 16 linked nucleosides and having themotif: kkk-d9-keke, wherein ‘d’ represents a 2′-deoxyribose sugar, ‘k’represents a cEt nucleoside, and ‘e’ represents a 2′-MOE nucleoside. Incertain embodiments, the cell is a cancer cell. In certain embodiments,the subject has cancer. In certain embodiments, administering thecompound to the subject treats the subject's cancer.

In certain embodiments, a method comprises contacting a cell oradministering to a subject a compound comprising a modifiedoligonucleotide consisting of 16 linked nucleosides and having themotif: kk-d9-kdkdk, wherein ‘d’ represents a 2′-deoxyribose sugar, ‘k’represents a cEt nucleoside, and ‘e’ represents a 2′-MOE nucleoside. Incertain embodiments, the cell is a cancer cell. In certain embodiments,the subject has cancer. In certain embodiments, administering thecompound to the subject treats the subject's cancer.

In certain embodiments, a compound comprises a modified oligonucleotideconsisting of 16 linked nucleosides and having the motif: kk-d9-eeekk,wherein ‘d’ represents a 2′-deoxyribose sugar, ‘k’ represents a cEtnucleoside, and ‘e’ represents a 2′-MOE nucleoside. In certainembodiments, a method comprises contacting a cell or administering to asubject a compound comprising a modified oligonucleotide consisting of16 linked nucleosides and having the motif: kk-d9-eeekk, wherein ‘d’represents a 2′-deoxyribose sugar, ‘k’ represents a cEt nucleoside, and‘e’ represents a 2′-MOE nucleoside. In certain embodiments, the cell isa cancer cell. In certain embodiments, the subject has cancer. Incertain embodiments, administering the compound to the subject treatsthe subject's cancer.

In certain embodiments, a method comprises contacting a cell oradministering to a subject a compound comprising a modifiedoligonucleotide consisting of 16 linked nucleosides and having themotif: kk-d9-ekeke, wherein ‘d’ represents a 2′-deoxyribose sugar, ‘k’represents a cEt nucleoside, and ‘e’ represents a 2′-MOE nucleoside. Incertain embodiments, the cell is a cancer cell. In certain embodiments,the subject has cancer. In certain embodiments, administering thecompound to the subject treats the subject's cancer.

b. Certain Nucleobase Motifs

In certain embodiments, compounds described herein compriseoligonucleotides. In certain embodiments, oligonucleotides comprisemodified and/or unmodified nucleobases arranged along theoligonucleotide or region thereof in a defined pattern or motif. Incertain embodiments, each nucleobase is modified. In certainembodiments, none of the nucleobases are modified. In certainembodiments, each purine or each pyrimidine is modified. In certainembodiments, each adenine is modified. In certain embodiments, eachguanine is modified. In certain embodiments, each thymine is modified.In certain embodiments, each uracil is modified. In certain embodiments,each cytosine is modified. In certain embodiments, some or all of thecytosine nucleobases in a modified oligonucleotide are5-methylcytosines.

In certain embodiments, modified oligonucleotides comprise a block ofmodified nucleobases. In certain such embodiments, the block is at the3′-end of the oligonucleotide. In certain embodiments the block iswithin 3 nucleosides of the 3′-end of the oligonucleotide. In certainembodiments, the block is at the 5′-end of the oligonucleotide. Incertain embodiments the block is within 3 nucleosides of the 5′-end ofthe oligonucleotide.

In certain embodiments, oligonucleotides having a gapmer motif comprisea nucleoside comprising a modified nucleobase. In certain suchembodiments, one nucleoside comprising a modified nucleobase is in thecentral gap of an oligonucleotide having a gapmer motif. In certain suchembodiments, the sugar moiety of said nucleoside is a 2′-deoxyribosylmoiety. In certain embodiments, the modified nucleobase is selectedfrom: a 2-thiopyrimidine and a 5-propynepyrimidine.

c. Certain Internucleoside Linkage Motifs

In certain embodiments, compounds described herein compriseoligonucleotides. In certain embodiments, oligonucleotides comprisemodified and/or unmodified internucleoside linkages arranged along theoligonucleotide or region thereof in a defined pattern or motif. Incertain embodiments, essentially each internucleoside linking group is aphosphate internucleoside linkage (P═O). In certain embodiments, eachinternucleoside linking group of a modified oligonucleotide is aphosphorothioate (P═S). In certain embodiments, each internucleosidelinking group of a modified oligonucleotide is independently selectedfrom a phosphorothioate and phosphate internucleoside linkage. Incertain embodiments, the sugar motif of a modified oligonucleotide is agapmer and the internucleoside linkages within the gap are all modified.In certain such embodiments, some or all of the internucleoside linkagesin the wings are unmodified phosphate linkages. In certain embodiments,the terminal internucleoside linkages are modified.

4. Certain Modified Oligonucleotides

In certain embodiments, compounds described herein comprise modifiedoligonucleotides. In certain embodiments, the above modifications(sugar, nucleobase, internucleoside linkage) are incorporated into amodified oligonucleotide. In certain embodiments, modifiedoligonucleotides are characterized by their modification, motifs, andoverall lengths. In certain embodiments, such parameters are eachindependent of one another. Thus, unless otherwise indicated, eachinternucleoside linkage of an oligonucleotide having a gapmer sugarmotif may be modified or unmodified and may or may not follow the gapmermodification pattern of the sugar modifications. For example, theinternucleoside linkages within the wing regions of a sugar gapmer maybe the same or different from one another and may be the same ordifferent from the internucleoside linkages of the gap region of thesugar motif. Likewise, such gapmer oligonucleotides may comprise one ormore modified nucleobase independent of the gapmer pattern of the sugarmodifications. Furthermore, in certain instances, an oligonucleotide isdescribed by an overall length or range and by lengths or length rangesof two or more regions (e.g., a regions of nucleosides having specifiedsugar modifications), in such circumstances it may be possible to selectnumbers for each range that result in an oligonucleotide having anoverall length falling outside the specified range. In suchcircumstances, both elements must be satisfied. For example, in certainembodiments, a modified oligonucleotide consists of 15-20 linkednucleosides and has a sugar motif consisting of three regions, A, B, andC, wherein region A consists of 2-6 linked nucleosides having aspecified sugar motif, region B consists of 6-10 linked nucleosideshaving a specified sugar motif, and region C consists of 2-6 linkednucleosides having a specified sugar motif. Such embodiments do notinclude modified oligonucleotides where A and C each consist of 6 linkednucleosides and B consists of 10 linked nucleosides (even though thosenumbers of nucleosides are permitted within the requirements for A, B,and C) because the overall length of such oligonucleotide is 22, whichexceeds the upper limit of the overall length of the modifiedoligonucleotide (20). Herein, if a description of an oligonucleotide issilent with respect to one or more parameter, such parameter is notlimited. Thus, a modified oligonucleotide described only as having agapmer sugar motif without further description may have any length,internucleoside linkage motif, and nucleobase motif. Unless otherwiseindicated, all modifications are independent of nucleobase sequence.

Certain Conjugated Compounds

In certain embodiments, the compounds described herein comprise orconsist of an oligonucleotide (modified or unmodified) and optionallyone or more conjugate groups and/or terminal groups. Conjugate groupsconsist of one or more conjugate moiety and a conjugate linker whichlinks the conjugate moiety to the oligonucleotide. Conjugate groups maybe attached to either or both ends of an oligonucleotide and/or at anyinternal position. In certain embodiments, conjugate groups are attachedto the 2′-position of a nucleoside of a modified oligonucleotide. Incertain embodiments, conjugate groups that are attached to either orboth ends of an oligonucleotide are terminal groups. In certain suchembodiments, conjugate groups or terminal groups are attached at the 3′and/or 5′-end of oligonucleotides. In certain such embodiments,conjugate groups (or terminal groups) are attached at the 3′-end ofoligonucleotides. In certain embodiments, conjugate groups are attachednear the 3′-end of oligonucleotides. In certain embodiments, conjugategroups (or terminal groups) are attached at the 5′-end ofoligonucleotides. In certain embodiments, conjugate groups are attachednear the 5′-end of oligonucleotides.

In certain embodiments, the oligonucleotide is modified. In certainembodiments, the oligonucleotide of a compound has a nucleobase sequencethat is complementary to a target nucleic acid. In certain embodiments,oligonucleotides are complementary to a messenger RNA (mRNA). In certainembodiments, oligonucleotides are complementary to a sense transcript.

Examples of terminal groups include but are not limited to conjugategroups, capping groups, phosphate moieties, protecting groups, modifiedor unmodified nucleosides, and two or more nucleosides that areindependently modified or unmodified.

A. Certain Conjugate Groups

In certain embodiments, oligonucleotides are covalently attached to oneor more conjugate groups. In certain embodiments, conjugate groupsmodify one or more properties of the attached oligonucleotide, includingbut not limited to pharmacodynamics, pharmacokinetics, stability,binding, absorption, tissue distribution, cellular distribution,cellular uptake, charge and clearance In certain embodiments, conjugategroups impart a new property on the attached oligonucleotide, e.g.,fluorophores or reporter groups that enable detection of theoligonucleotide.

Certain conjugate groups and conjugate moieties have been describedpreviously, for example: cholesterol moiety (Letsinger et al., Proc.Natl. Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid (Manoharan etal., Bioorg. Med. Chem. Lett., 1994, 4, 1053-1060), a thioether, e.g.,hexyl-S-tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660,306-309; Manoharan et al., Bioorg. Med. Chem. Lett., 1993, 3,2765-2770), a thiocholesterol (Oberhauser et al., Nucl. Acids Res.,1992, 20, 533-538), an aliphatic chain, e.g., do-decan-diol or undecylresidues (Saison-Behmoaras et al., EMBO 1, 1991, 10, 1111-1118; Kabanovet al., FEBS Lett., 1990, 259, 327-330; Svinarchuk et al., Biochimie,1993, 75, 49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol ortriethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate(Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654; Shea et al.,Nucl. Acids Res., 1990, 18, 3777-3783), a polyamine or a polyethyleneglycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14,969-973), or adamantane acetic, a palmityl moiety (Mishra et al.,Biochim. Biophys. Acta, 1995, 1264, 229-237), an octadecylamine orhexylamino-carbonyl-oxycholesterol moiety (Crooke et al., J. Pharmacol.Exp. Ther., 1996, i, 923-937), a tocopherol group (Nishina et al.,Molecular Therapy Nucleic Acids, 2015, 4, e220; doi:10.1038/mtna.2014.72and Nishina et al., Molecular Therapy, 2008, 16, 734-740), or a GalNAccluster (e.g., WO2014/179620).

1. Conjugate Moieties

Conjugate moieties include, without limitation, intercalators, reportermolecules, polyamines, polyamides, peptides, carbohydrates (e.g.,GalNAc), vitamin moieties, polyethylene glycols, thioethers, polyethers,cholesterols, thiocholesterols, cholic acid moieties, folate, lipids,phospholipids, biotin, phenazine, phenanthridine, anthraquinone,adamantane, acridine, fluoresceins, rhodamines, coumarins, fluorophores,and dyes.

In certain embodiments, a conjugate moiety comprises an active drugsubstance, for example, aspirin, warfarin, phenylbutazone, ibuprofen,suprofen, fen-bufen, ketoprofen, (S)-(+)-pranoprofen, carprofen,dansylsarcosine, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid,folinic acid, a benzothiadiazide, chlorothiazide, a diazepine,indo-methicin, a barbiturate, a cephalosporin, a sulfa drug, anantidiabetic, an antibacterial or an antibiotic.

2. Conjugate Linkers

Conjugate moieties are attached to oligonucleotides through conjugatelinkers. In certain compounds, a conjugate group is a single chemicalbond (i.e. conjugate moiety is attached to an oligonucleotide via aconjugate linker through a single bond). In certain embodiments, theconjugate linker comprises a chain structure, such as a hydrocarbylchain, or an oligomer of repeating units such as ethylene glycol,nucleosides, or amino acid units.

In certain embodiments, a conjugate linker comprises one or more groupsselected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol,ether, thioether, and hydroxylamino. In certain such embodiments, theconjugate linker comprises groups selected from alkyl, amino, oxo, amideand ether groups. In certain embodiments, the conjugate linker comprisesgroups selected from alkyl and amide groups. In certain embodiments, theconjugate linker comprises groups selected from alkyl and ether groups.In certain embodiments, the conjugate linker comprises at least onephosphorus moiety. In certain embodiments, the conjugate linkercomprises at least one phosphate group. In certain embodiments, theconjugate linker includes at least one neutral linking group.

In certain embodiments, conjugate linkers, including the conjugatelinkers described above, are bifunctional linking moieties, e.g., thoseknown in the art to be useful for attaching conjugate groups to parentcompounds, such as the oligonucleotides provided herein. In general, abifunctional linking moiety comprises at least two functional groups.One of the functional groups is selected to bind to a particular site ona compound and the other is selected to bind to a conjugate group.Examples of functional groups used in a bifunctional linking moietyinclude but are not limited to electrophiles for reacting withnucleophilic groups and nucleophiles for reacting with electrophilicgroups. In certain embodiments, bifunctional linking moieties compriseone or more groups selected from amino, hydroxyl, carboxylic acid,thiol, alkyl, alkenyl, and alkynyl.

Examples of conjugate linkers include but are not limited topyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) and6-aminohexanoic acid (AHEX or AHA). Other conjugate linkers include butare not limited to substituted or unsubstituted C₁-C₁₀ alkyl,substituted or unsubstituted C₂-C₁₀ alkenyl or substituted orunsubstituted C₂-C₁₀ alkynyl, wherein a nonlimiting list of preferredsubstituent groups includes hydroxyl, amino, alkoxy, carboxy, benzyl,phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl andalkynyl.

In certain embodiments, conjugate linkers comprise 1-10linker-nucleosides. In certain embodiments, such linker-nucleosides aremodified nucleosides. In certain embodiments such linker-nucleosidescomprise a modified sugar moiety. In certain embodiments,linker-nucleosides are unmodified. In certain embodiments,linker-nucleosides comprise an optionally protected heterocyclic baseselected from a purine, substituted purine, pyrimidine or substitutedpyrimidine. In certain embodiments, a cleavable moiety is a nucleosideselected from uracil, thymine, cytosine, 4-N-benzoylcytosine,5-methylcytosine, 4-N-benzoyl-5-methylcytosine, adenine,6-N-benzoyladenine, guanine and 2-N-isobutyrylguanine. It is typicallydesirable for linker-nucleosides to be cleaved from the compound afterit reaches a target tissue. Accordingly, linker-nucleosides aretypically linked to one another and to the remainder of the compoundthrough cleavable bonds. In certain embodiments, such cleavable bondsare phosphodiester bonds.

Herein, linker-nucleosides are not considered to be part of theoligonucleotide. Accordingly, in embodiments in which a compoundcomprises an oligonucleotide consisting of a specified number or rangeof linked nucleosides and/or a specified percent complementarity to areference nucleic acid and the compound also comprises a conjugate groupcomprising a conjugate linker comprising linker-nucleosides, thoselinker-nucleosides are not counted toward the length of theoligonucleotide and are not used in determining the percentcomplementarity of the oligonucleotide for the reference nucleic acid.For example, a compound may comprise (1) a modified oligonucleotideconsisting of 8-30 nucleosides and (2) a conjugate group comprising 1-10linker-nucleosides that are contiguous with the nucleosides of themodified oligonucleotide. The total number of contiguous linkednucleosides in such a compound is more than 30. Alternatively, ancompound may comprise a modified oligonucleotide consisting of 8-30nucleosides and no conjugate group. The total number of contiguouslinked nucleosides in such a compound is no more than 30. Unlessotherwise indicated conjugate linkers comprise no more than 10linker-nucleosides. In certain embodiments, conjugate linkers compriseno more than 5 linker-nucleosides. In certain embodiments, conjugatelinkers comprise no more than 3 linker-nucleosides. In certainembodiments, conjugate linkers comprise no more than 2linker-nucleosides. In certain embodiments, conjugate linkers compriseno more than 1 linker-nucleoside.

In certain embodiments, it is desirable for a conjugate group to becleaved from the oligonucleotide. For example, in certain circumstancescompounds comprising a particular conjugate moiety are better taken upby a particular cell type, but once the compound has been taken up, itis desirable that the conjugate group be cleaved to release theunconjugated or parent oligonucleotide. Thus, certain conjugate maycomprise one or more cleavable moieties, typically within the conjugatelinker. In certain embodiments, a cleavable moiety is a cleavable bond.In certain embodiments, a cleavable moiety is a group of atomscomprising at least one cleavable bond. In certain embodiments, acleavable moiety comprises a group of atoms having one, two, three,four, or more than four cleavable bonds. In certain embodiments, acleavable moiety is selectively cleaved inside a cell or subcellularcompartment, such as a lysosome. In certain embodiments, a cleavablemoiety is selectively cleaved by endogenous enzymes, such as nucleases.

In certain embodiments, a cleavable bond is selected from among: anamide, an ester, an ether, one or both esters of a phosphodiester, aphosphate ester, a carbamate, or a disulfide. In certain embodiments, acleavable bond is one or both of the esters of a phosphodiester. Incertain embodiments, a cleavable moiety comprises a phosphate orphosphodiester. In certain embodiments, the cleavable moiety is aphosphate linkage between an oligonucleotide and a conjugate moiety orconjugate group.

In certain embodiments, a cleavable moiety comprises or consists of oneor more linker-nucleosides. In certain such embodiments, one or morelinker-nucleosides are linked to one another and/or to the remainder ofthe compound through cleavable bonds. In certain embodiments, suchcleavable bonds are unmodified phosphodiester bonds. In certainembodiments, a cleavable moiety is 2′-deoxy nucleoside that is attachedto either the 3′ or 5′-terminal nucleoside of an oligonucleotide by aphosphate internucleoside linkage and covalently attached to theremainder of the conjugate linker or conjugate moiety by a phosphate orphosphorothioate linkage. In certain such embodiments, the cleavablemoiety is 2′-deoxyadenosine.

Compositions and Methods for Formulating Pharmaceutical Compositions

Compounds described herein may be admixed with pharmaceuticallyacceptable active or inert substances for the preparation ofpharmaceutical compositions or formulations. Compositions and methodsfor the formulation of pharmaceutical compositions are dependent upon anumber of criteria, including, but not limited to, route ofadministration, extent of disease, or dose to be administered.

Certain embodiments provide pharmaceutical compositions comprising oneor more compounds or a salt thereof. In certain embodiments, thecompounds are antisense compounds or oligomeric compounds. In certainembodiments, the compounds comprise or consist of a modifiedoligonucleotide. In certain such embodiments, the pharmaceuticalcomposition comprises a suitable pharmaceutically acceptable diluent orcarrier. In certain embodiments, a pharmaceutical composition comprisesa sterile saline solution and one or more compound. In certainembodiments, such pharmaceutical composition consists of a sterilesaline solution and one or more compound. In certain embodiments, thesterile saline is pharmaceutical grade saline. In certain embodiments, apharmaceutical composition comprises one or more compound and sterilewater. In certain embodiments, a pharmaceutical composition consists ofone compound and sterile water. In certain embodiments, the sterilewater is pharmaceutical grade water. In certain embodiments, apharmaceutical composition comprises one or more compound andphosphate-buffered saline (PBS). In certain embodiments, apharmaceutical composition consists of one or more compound and sterilePBS. In certain embodiments, the sterile PBS is pharmaceutical gradePBS. Compositions and methods for the formulation of pharmaceuticalcompositions are dependent upon a number of criteria, including, but notlimited to, route of administration, extent of disease, or dose to beadministered.

A compound described herein targeted to MALAT1 nucleic acid can beutilized in pharmaceutical compositions by combining the compound with asuitable pharmaceutically acceptable diluent or carrier. In certainembodiments, a pharmaceutically acceptable diluent is water, such assterile water suitable for injection. Accordingly, in one embodiment,employed in the methods described herein is a pharmaceutical compositioncomprising a compound targeted to MALAT1 nucleic acid and apharmaceutically acceptable diluent. In certain embodiments, thepharmaceutically acceptable diluent is water. In certain embodiments,the compound comprises or consists of a modified oligonucleotideprovided herein.

Pharmaceutical compositions comprising compounds provided hereinencompass any pharmaceutically acceptable salts, esters, or salts ofsuch esters, or any other oligonucleotide which, upon administration toan animal, including a human, is capable of providing (directly orindirectly) the biologically active metabolite or residue thereof. Incertain embodiments, the compounds are antisense compounds or oligomericcompounds. In certain embodiments, the compound comprises or consists ofa modified oligonucleotide. Accordingly, for example, the disclosure isalso drawn to pharmaceutically acceptable salts of compounds, prodrugs,pharmaceutically acceptable salts of such prodrugs, and otherbioequivalents. Suitable pharmaceutically acceptable salts include, butare not limited to, sodium and potassium salts.

A prodrug can include the incorporation of additional nucleosides at oneor both ends of a compound which are cleaved by endogenous nucleaseswithin the body, to form the active compound.

In certain embodiments, the compounds or compositions further comprise apharmaceutically acceptable carrier or diluent.

EXAMPLES

Non-Limiting Disclosure and Incorporation by Reference

Although the sequence listing accompanying this filing identifies eachsequence as either “RNA” or “DNA” as required, in reality, thosesequences may be modified with any combination of chemicalmodifications. One of skill in the art will readily appreciate that suchdesignation as “RNA” or “DNA” to describe modified oligonucleotides is,in certain instances, arbitrary. For example, an oligonucleotidecomprising a nucleoside comprising a 2′-OH sugar moiety and a thyminebase could be described as a DNA having a modified sugar (2′-OH for thenatural 2′-H of DNA) or as an RNA having a modified base (thymine(methylated uracil) for natural uracil of RNA).

Accordingly, nucleic acid sequences provided herein, including, but notlimited to those in the sequence listing, are intended to encompassnucleic acids containing any combination of natural or modified RNAand/or DNA, including, but not limited to such nucleic acids havingmodified nucleobases. By way of further example and without limitation,an oligonucleotide having the nucleobase sequence “ATCGATCG” encompassesany oligonucleotides having such nucleobase sequence, whether modifiedor unmodified, including, but not limited to, such compounds comprisingRNA bases, such as those having sequence “AUCGAUCG” and those havingsome DNA bases and some RNA bases such as “AUCGATCG” and compoundshaving other modified nucleobases, such as “AT^(m)CGAUCG,” wherein ^(m)Cindicates a cytosine base comprising a methyl group at the 5-position.

While certain compounds, compositions and methods described herein havebeen described with specificity in accordance with certain embodiments,the following examples serve only to illustrate the compounds describedherein and are not intended to limit the same. Each of the referencesrecited in the present application is incorporated herein by referencein its entirety.

Example 1: Design of Gapmers with PS Internucleoside LinkagesComplementary to Human MALAT1 RNA

Modified oligonucleotides complementary to human a MALAT1 nucleic acidwere designed. The modified oligonucleotides in the table below are3-10-3 cET gapmers. The gapmers are 16 nucleosides in length, whereinthe central gap segment comprises of either ten 2′-deoxynucleosides, orof a combination of one 2′-O-methyl nucleoside and nine2′-deoxynucleosides. The central gap segment is flanked by wing segmentson the 5′ direction and the 3′ direction comprising three nucleosideseach. Each nucleoside in the 5′ wing segment and each nucleoside in the3′ wing segment has a cEt sugar modification. The internucleosidelinkages throughout each gapmer are phosphorothioate (P═S) linkages.Each cytosine residue is a 5-methylcytosine. The sequence and chemicalnotation column specifies the sequence, including 5-methylcytosines,sugar chemistry, and the internucleoside linkage chemistry; whereinsubscript ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, subscript‘k’ represents a cET sugar moiety, subscript ‘s’ represents to aphosphorothioate internucleoside linkage, superscript ‘m’ before thecytosine residue represents a 5-methylcytosine, and subscript ‘y’represents a 2′-O-methyl ribose sugar. “Start site” indicates the5′-most nucleoside to which the gapmer is complementary in the humannucleic acid sequence. “Stop site” indicates the 3′-most nucleoside towhich the gapmer is complementary in the human nucleic acid sequence.

Each modified oligonucleotide listed in the table below is complementaryto human MALAT1 nucleic acid sequence SEQ ID NO: 1 (GENBANK AccessionNo: XR_001309.1).

TABLE 1cET gapmers with PS internucleoside linkages complementary to human MALAT1SEQ ID SEQ ID NO: 1 NO: 1 SEQ Compound Sequence Start Stop ID Number(5′ to 3′) Site Site Chemistry Notation (5′ to 3′) NO 1157034TTCGGTTTAATCTCTT 1535 1550 T_(ks)T_(ks)^(m)C_(ks)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)T_(ds)^(m)C_(ds)T_(ds) ^(m)C_(ks)T_(ks)T_(k)  2 1157111 GGTTACCAATAATTTC 20342049 G_(ks)G_(ks)T_(ks)T_(ds)A_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(ds)T_(ds)A_(ds)A_(ds)T_(ds)T_(ks)T_(ks) ^(m)C_(k)  31157190 TGGTAATTACTCTTGA 2341 2356T_(ks)G_(ks)G_(ks)T_(ds)A_(ds)A_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ks)G_(ks)A_(k)   4 1157929 GTAGTAAGAATCTCAG 4821 4836G_(ks)T_(ks)A_(ks)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)A_(ds)A_(ds)T_(ds)mC_(ds)T_(ds)^(m)C_(ks)A_(ks)G_(k)  5 1158161 CCTTAGTTGGCATCAA 5494 5509 ^(m)C_(ks)^(m)C_(ks)T_(ks)T_(ds)A_(ds)G_(ds)T_(ds)T_(ds)G_(ds)G_(ds)^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ks)A_(ks)A_(k)  6 1158162 TCCTTAGTTGGCATCA5495 5510 T_(ks) ^(m)C_(ks)^(m)C_(ks)T_(ds)T_(ds)A_(ds)G_(ds)T_(ds)T_(ds)G_(ds)G_(ds)^(m)C_(ds)A_(ds)T_(ks) ^(m)C_(ks)A_(k)  7 1304884 GGATUAATGTAGTGTA 50495064G_(ks)G_(ks)A_(ks)T_(ds)U_(ys)A_(ds)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)G_(ds)T_(ds)G_(ks)T_(ks)A_(k) 8 1304890 GGTTATAGCTTGACAA 4931 4946G_(ks)G_(ks)T_(ks)T_(ds)A_(ys)T_(ds)A_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ks)A_(ks)A_(k)  9 1304906GCAGATAATGTTCTCA 4840 4855 G_(ks)^(m)C_(ks)A_(ks)G_(ds)A_(ys)T_(ds)A_(ds)A_(ds)T_(ds)G_(ds)T_(ds)T_(ds)^(m)C_(ds)T_(ks) ^(m)C_(ks)A_(k) 10

Example 2: Antisense Inhibition of Human MALAT1 in A-431 Cells byModified Oligonucleotides

The modified oligonucleotides were tested in a series of experimentsthat had similar culture conditions. The results for each experiment arepresented in a single table shown below. Cultured A-431 cells at adensity of 10,000 cells per well were treated using free uptake with 5nM of modified oligonucleotide. After a treatment period ofapproximately 48 hours, RNA was isolated from the cells and MALAT1 RNAlevels were measured by quantitative real-time RTPCR. Human primer probeset RTS2736 (forward sequence AAAGCAAGGTCTCCCCACAAG, designated hereinas SEQ ID NO.: 2814; reverse sequence TGAAGGGTCTGTGCTAGATCAAAA,designated herein as SEQ ID NO.: 2815; probe sequenceTGCCACATCGCCACCCCGT, designated herein as SEQ ID NO.: 2816) was used tomeasure RNA levels. MALAT1 RNA levels were normalized to total RNAcontent, as measured by RIBOGREEN®. Results are presented in the tablesbelow as percent control of the amount of MALAT1 RNA relative tountreated control cells (% UTC).

TABLE 2 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers targeting SEQ IDNO.: 1 Compound Number % UTC 1157034 25 1157111 11 1157190 19 1157929 201158161 18 1158162 24

Example 3: Dose-Dependent Inhibition of Human MALAT1 in A-431 Cells bycEt Gapmers

Modified oligonucleotides described in the studies above were tested atvarious doses in A-431 cells. Cultured A-431 cells at a density of10,000 cells per well were treated using free uptake with modifiedoligonucleotides diluted to concentrations described in the tablesbelow. After approximately 48 hours, MALAT1 RNA levels were measured aspreviously described using the Human MALAT1 primer-probe set RTS2736.MALAT1 RNA levels were normalized to total RNA content, as measured byRIBOGREEN®. Results are presented in the tables below as percent controlof the amount of MALAT1 RNA relative to untreated control cells (% UTC).IC50s were calculated using a linear regression on a log/linear plot ofthe data in excel.

TABLE 3 Dose-dependent inhibition of human MALAT1 mRNA expression bymodified oligonucleotides in A-431 Compound % control IC50 Number 0.3 nM1.25 nM 5.0 nM 20.0 nM (nM) 1157034 72 57 26 6 1 1157111 108 73 6 7 21157190 89 93 58 18 6 1157929 81 76 29 10 2 1158161 83 77 37 9 3 115816282 78 32 10 3

Example 4: Dose-Dependent Inhibition of Human MALAT1 in MDA-MB-436 Cellsby cEt Gapmers

Modified oligonucleotides described in the studies above were tested atvarious doses in MDA-MB-436 cells. Cultured MDA-MB-436 cells at adensity of 5,000-12,000 cells per well were treated using free uptakewith modified oligonucleotides diluted to concentrations described inthe tables below. After approximately 48 hours, MALAT1 RNA levels weremeasured as previously described using the Human MALAT1 primer-probe setRTS2736. MALAT1 RNA levels were normalized to b-actin, measured usinghuman primer-probe set HTS5002 (forward sequenceCGGACTATGACTTAGTTGCGTTACA, designated herein as SEQ ID NO.: 2817;reverse sequence GCCATGCCAATCTCATCTTGT, designated herein as SEQ ID NO.:2818; probe sequence CCTTTCTTGACAAAACCTAACTTGCGCAGA, designated hereinas SEQ ID NO.: 2819). Results are presented in the tables below aspercent control of the amount of MALAT1 RNA relative to untreatedcontrol cells (% UTC). Each table below represents a separateexperiment. IC50s for table 4 were calculated using the “log(inhibitor)vs. response—variable slope (4 parameters)” formula using Prism6software. IC50s for tables 5 and 6 were calculated using the“log(inhibitor) vs. response—variable slope (3 parameters)” formulausing Prism7 software.

TABLE 4 Dose-dependent inhibition of human MALAT1 RNA expression bymodified oligonucleotides in MDA-MB-436 cells Compound % control IC50Number 0.8 nM 4.0 nM 20.0 nM 100.0 nM (nM) 1157034 50 25 17 5 0.71157111 98 30 13 8 2.9 1157190 56 39 15 5 1.4 1157929 58 51 33 5 2.61158161 36 48 27 3 0.5 1158162 57 37 22 6 1.5

TABLE 5 Dose-dependent inhibition of human MALAT1 RNA expression bymodified oligonucleotides in MDA-MB-436 cells Compound % control IC50Number 8 nM 40 nM 200 nM 1000 nM (nM) 1304906 68 23 6 2 8 1304890 68 205 3 5 1304884 68 25 5 2 10

TABLE 6 Dose-dependent inhibition of human MALAT1 RNA expression bymodified oligonucleotides in MDA-MB-436 cells Compound % control IC50Number 0.4 nM 2 nM 10 nM 50 nM (nM) 1304906 98 88 47 17 9 1304890 109 8852 17 8 1304884 98 75 55 23 8

Example 5: Tolerability of Modified Oligonucleotides Targeting HumanMALAT1 in CD-1 Mice

CD-1 mice were treated with modified oligonucleotides selected fromstudies described above and evaluated for changes in the levels ofvarious plasma chemistry markers.

Treatment

Groups of male CD-1 mice at 4-6 weeks of age (obtained from CharlesRiver) were injected subcutaneously twice a week for four weeks (for atotal of 8 treatments) with 50 mg/kg of modified oligonucleotides. Onegroup of male CD-1 mice was injected with PBS. Mice were euthanized 25days post start of treatment (24 hours post final administration).

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function,plasma levels of alanine aminotransferase (ALT), aspartateaminotransferase (AST), blood urea nitrogen (BUN), total bilirubin(TBIL), and albumin (ALB) were measured using an automated clinicalchemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). The resultsare presented in the tables below.

TABLE 7 Plasma chemistry markers in CD-1 mice ALT AST BUN TBIL AlbuminION NO. (IU/L) (IU/L) (mg/dL) (mg/dL) (g/dL) PBS 20 46 24 0.2 2.51157929 330 225 24 0.2 2.3 1158161 86 128 29 0.2 2.3Body and Organ Weights

Body weights of CD-1 mice were measured at the end of the study, and theaverage body weight for each group is presented in the table below.Kidney, spleen, and liver weights were measured at the end of the studyand are presented in the table below.

TABLE 8 Body and organ weights Body Weight Liver Kidney Spleen ION No.(g) (g) (g) (g) PBS 32 1.7 0.5 0.1 1157929 34 2.3 0.5 0.2 1158161 34 2.30.5 0.2

Example 6: Tolerability of Modified Oligonucleotides Targeting HumanMALAT1 in CD-1 Mice

CD-1 mice were treated with modified oligonucleotides selected fromstudies described above and evaluated for changes in the levels ofvarious plasma chemistry markers.

Treatment

Groups of male CD-1 mice at 4-6 weeks of age (obtained from CharlesRiver) were injected subcutaneously twice a week for four weeks (for atotal of 8 treatments) with 50 mg/kg of modified oligonucleotides. Onegroup of male CD-1 mice was injected with PBS. Mice were euthanized 24days post start of treatment (24 hours post final administration).

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function,plasma levels of alanine aminotransferase (ALT), aspartateaminotransferase (AST), blood urea nitrogen (BUN), and total bilirubin(TBIL), were measured using an automated clinical chemistry analyzer(Hitachi Olympus AU400c, Melville, N.Y.). The results are presented inthe tables below.

TABLE 9 Plasma chemistry markers in CD-1 mice ALT AST BUN TBIL ION NO.(IU/L) (IU/L) (mg/dL) (mg/dL) PBS 43 71 26 0.2 1157111 341 200 22 0.2Body and Organ Weights

Body weights of CD-1 mice were measured at the end of the study, and theaverage body weight for each group is presented in the table below.Kidney, spleen, and liver weights were measured at the end of the studyand are presented in the table below.

TABLE 10 Body and organ weights Body Weight Liver Kidney Spleen ION No.(g) (g) (g) (g) PBS 37 2.0 0.6 0.1 1157111 38 2.8 0.5 0.2

Example 7: Tolerability of Modified Oligonucleotides Targeting HumanMALAT1 in CD-1 Mice

CD-1 mice were treated with modified oligonucleotides selected fromstudies described above and evaluated for changes in the levels ofvarious plasma chemistry markers.

Treatment

Groups of male CD-1 mice at 4-6 weeks of age (obtained from CharlesRiver) were injected subcutaneously twice a week for four weeks (for atotal of 8 treatments) with 50 mg/kg of modified oligonucleotides. Onegroup of male CD-1 mice was injected with PBS. Mice were euthanized 26days post start of treatment (24 hours post final administration).

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function,plasma levels of alanine aminotransferase (ALT), aspartateaminotransferase (AST), blood urea nitrogen (BUN), and total bilirubin(TBIL), were measured using an automated clinical chemistry analyzer(Hitachi Olympus AU400c, Melville, N.Y.). The results are presented inthe tables below.

TABLE 11 Plasma chemistry markers in CD-1 mice ALT AST BUN TBIL ION NO.(IU/L) (IU/L) (mg/dL) (mg/dL) PBS 22 46 22 0.3 1157034 608 480 21 0.21157190 41 83 23 0.2 1158162 435 325 24 0.2Body and Organ Weights

Body weights of CD-1 mice were measured at the end of the study, and theaverage body weight for each group is presented in the table below.Kidney, spleen, and liver weights were measured at the end of the studyand are presented in the table below.

TABLE 12 Body and organ weights Body Weight Liver Kidney Spleen ION No.(g) (g) (g) (g) PBS 33 1.8 0.5 0.1 1157034 37 2.3 0.5 0.2 1157190 35 1.90.4 0.2 1158162 36 2.6 0.5 0.2

Example 8: Tolerability of Modified Oligonucleotides Targeting HumanMALAT1 in CD-1 Mice

CD-1 mice were treated with modified oligonucleotides selected fromstudies described above and evaluated for changes in the levels ofvarious plasma chemistry markers.

Treatment

Groups of male CD-1 mice at 4-6 weeks of age (obtained from CharlesRiver) were injected subcutaneously twice a week for four weeks (for atotal of 8 treatments) with 50 mg/kg of modified oligonucleotides. Onegroup of male CD-1 mice was injected with PBS. Mice were euthanized 25days post start of treatment (24 hours following the finaladministration).

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function,plasma levels of alanine aminotransferase (ALT), aspartateaminotransferase (AST), blood urea nitrogen (BUN), and total bilirubin(TBIL), were measured using an automated clinical chemistry analyzer(Hitachi Olympus AU400c, Melville, N.Y.). The results are presented inthe tables below.

TABLE 13 Plasma chemistry markers in CD-1 mice ALT AST BUN TBIL ION NO.(IU/L) (IU/L) (mg/dL) (mg/dL) PBS 20 51 21 0.2 1304890 33 51 21 0.21304906 59 78 22 0.2Body and Organ Weights

Body weights of CD-1 mice were measured at the end of the study, and theaverage body weight for each group is presented in the table below.Kidney, spleen, and liver weights were measured at the end of the studyand are presented in the table below.

TABLE 14 Body and organ weights Body Weight Liver Kidney Spleen ION No.(g) (g) (g) (g) PBS 32 1.6 0.5 0.1 1304890 36 2.0 0.5 0.2 1304906 34 1.80.5 0.1

Example 9: Tolerability of Modified Oligonucleotides Targeting HumanMALAT1 in CD-1 Mice

CD-1 mice were treated with modified oligonucleotides selected fromstudies described above and evaluated for changes in the levels ofvarious plasma chemistry markers.

Treatment

Groups of male CD-1 mice at 4-6 weeks of age (obtained from CharlesRiver) were injected subcutaneously twice a week for four weeks (for atotal of 8 treatments) with 50 mg/kg of modified oligonucleotides. Onegroup of male CD-1 mice was injected with PBS. Mice were euthanized 25days post start of treatment (24 hours following the finaladministration).

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function,plasma levels of alanine aminotransferase (ALT), aspartateaminotransferase (AST), blood urea nitrogen (BUN), and total bilirubin(TBIL), were measured using an automated clinical chemistry analyzer(Hitachi Olympus AU400c, Melville, N.Y.). The results are presented inthe tables below.

TABLE 15 Plasma chemistry markers in CD-1 mice ALT AST BUN TBIL ION NO.(IU/L) (IU/L) (mg/dL) (mg/dL) PBS 19 56 16 0.2 1304884 33 55 15 0.1Body and Organ Weights

Body weights of CD-1 mice were measured at the end of the study, and theaverage body weight for each group is presented in the table below.Kidney, spleen, and liver weights were measured at the end of the studyand are presented in the table below.

TABLE 16 Body and organ weights Body Weight Liver Kidney Spleen ION No.(g) (g) (g) (g) PBS 34 2.0 0.5 0.1 1304884 37 2.2 0.5 0.2

Example 10: Effect of Modified Oligonucleotides Targeting Human MALAT1in Cynomolgus Monkeys

Cynomolgus monkeys were treated with certain Ionis modifiedoligonucleotides selected from studies described in the Examples above.Modified oligonucleotide tolerability was evaluated.

Study 1

Treatment

Prior to the study, the monkeys were kept in quarantine during which theanimals were observed daily for general health. The monkeys were 2-4years old and weighed 2-4 kg. Seven groups of 4 randomly assigned malecynomolgus monkeys each were injected subcutaneously with Ionisoligonucleotide or saline in a clockwise rotation between four differentsites on the back. Following loading doses on days 1, 3, 5 and 7, themonkeys were dosed once per week for 6 weeks (on days 14, 21, 28, 35,and 41) with 35 mg/kg of Ionis oligonucleotide. A control group of 4cynomolgus monkeys was injected with 0.9% saline in a similar manner andserved as the control group.

During the study period, the monkeys were observed at least once dailyfor signs of illness or distress. Any animal experiencing illness ordistress was promptly reported to the veterinarian and Study Director.Any animal in poor health or in a possible moribund condition wasidentified for further monitoring and possible euthanasia Scheduledeuthanasia of the animals was conducted on day 43 approximately 48 hoursafter the last dose by exsanguination while under deep anesthesia. Theprotocols described in the Example were approved by the InstitutionalAnimal Care and Use Committee (IACUC).

Body and Organ Weight Measurements

To evaluate the effect of modified oligonucleotides on the overallhealth of the animals, body and organ weights were measured. Terminalbody weight was measured prior to necropsy. Organ weights were measuredas well.

TABLE 17 Body and organ weights (g) Compound Body Weight No. (g) Day 43Heart kidney spleen liver Saline 2565 10 12 3 49 1157034 2748 10 16 5 671157111 2524 9 13 3 62 1157190 2663 10 15 5 63 1157929 2655 10 14 3 591158161 2418 9 14 3 53 1158162 2499 9 18 3 55Kidney and Liver Function

To evaluate the effect of modified oligonucleotides on hepatic andkidney function, blood samples were collected from all the study groupson day 43. The monkeys were fasted overnight prior to blood collection.Blood was collected in tubes without anticoagulant for serum separation.The tubes were kept at room temperature for a minimum of 90 minutes andthen centrifuged at 3000 rpm for 10 minutes to obtain serum. Levels ofvarious liver function markers were measured using a Toshiba 120FR NEOchemistry analyzer (Toshiba Co., Japan). Plasma levels of blood ureanitrogen (BUN), creatinine (CREA), total protein (TP), alanineaminotransferase (ALT), aspartate aminotransferase (AST), and totalbilirubin (TBIL) were measured.

TABLE 18 Liver function markers in cynomolgus monkey plasma Compound ALTAST BUN CREA TP TBIL No. (IU/L) (IU/L) (mg/dL) (mg/dL) (g/dL) (mg/dL)Saline 49 59 21 0.9 7.3 0.3 1157034 40 55 18 0.8 6.8 0.2 1157111 41 7223 0.8 7.1 0.3 1157190 59 67 21 0.9 7.1 0.3 1157929 63 71 21 0.9 7.1 0.21158161 58 59 18 0.8 7.3 0.3 1158162 53 81 17 0.8 7.5 0.3Pro-Inflammatory Proteins Analysis

To evaluate any inflammatory effect of modified oligonucleotides incynomolgus monkeys, blood samples were taken for analysis. The monkeyswere fasted overnight prior to blood collection. On day 41 (pre-dose and24 hours post-dose), approximately 0.8 mL of blood was collected fromeach animal and put into tubes without anticoagulant for serumseparation. The tubes were kept at room temperature for a minimum of 90min and then centrifuged at 3,000 rpm for 10 min at room temperature toobtain serum. Complement C3 were measured using a Toshiba 120 FR NEOchemistry analyzer (Toshiba Co., Japan). Another marker of inflammation,C-Reactive Protein (CRP) was tested together with the clinical chemistryparameters tested for liver function above.

TABLE 19 Pro-inflammatory protein analysis in cynomolgus monkeysComplement C3 (mg/dL) CRP Compound Day 41 Day 41 (24 hr (mg/L) No.(pre-dose) post-dose) day 43 Saline 95 92 5 1157034 115 100 3 1157111105 87 9 1157190 106 90 4 1157929 115 105 7 1158161 107 99 5 1158162 111100 6Hematology

To evaluate any effect of modified oligonucleotides in cynomolgusmonkeys on hematologic parameters, blood samples of approximately 0.5 mLof blood was collected from each of the available study animals on day43. The samples were collected in tubes containing K₂-EDTA. Samples wereanalyzed for red blood cell (RBC) count, Hemoglobin (HGB), Hematocrit(HCT), platelet count (PLT), total white blood cell count (WBC),neutrophil counts (NEU), lymphocyte counts (LYM), and monocyte counts(MON) using an ADVIA2120i hematology analyzer (Siemens, USA).

TABLE 20 Hematological marker analysis in cynomolgus monkeys CompoundRBC HGB HCT PLT WBC NEU LYM MON No. (×106/μL) (g/dL) (%) (10³/μL)(×10³/μL) (%) (%) (%) Saline 5 12 43 320 8 47 49 3 1157034 6 13 45 32911 34 61 4 1157111 5 13 43 419 13 50 45 3 1157190 6 13 44 383 10 38 56 41157929 6 13 45 309 8 37 57 3 1158161 6 13 43 332 11 31 63 3 1158162 512 43 453 9 41 52 5Urine Analysis

Food was removed overnight the day before fresh urine collection, butwater was supplied. Fresh urine samples for urinalysis and urinechemistry were collected from all animals using a clean cage pan on wetice (first in the morning) on day 43. Urinalysis/Urine Chemistryparameters creatinine (UCRE), microprotein (UTP), urine microalbumin(UALB), and protein/creatinine (P/C) ratio were measured using a Toshiba120FR automated chemistry analyzer (Toshiba Co., Japan).

TABLE 21 Urine analysis in cynomolgus monkeys Compound UCRE UTP UALB P/CNo. (mg/dL) (mg/dL) (mg/dL) ratio Saline 98 14 0.75 0.15 1157034 44 160.34 0.39 1157111 46 13 0.30 0.29 1157190 64 17 0.29 0.28 1157929 83 130.56 0.17 1158161 111 18 0.70 0.17 1158162 45 26 5.10 0.65Study 2Treatment

Prior to the study, the monkeys were kept in quarantine during which theanimals were observed daily for general health. The monkeys were 2-4years old and weighed 2-4 kg. Four groups of 4 randomly assigned malecynomolgus monkeys each were injected subcutaneously with Ionisoligonucleotide or saline in a clockwise rotation between four differentsites on the back. Following loading doses on days 1, 3, 5 and 7, themonkeys were dosed once per week for 6 weeks (on days 14, 21, 28, 35,and 41) with 35 mg/kg of Ionis oligonucleotide. A control group of 4cynomolgus monkeys was injected with 0.9% saline in a similar manner andserved as the control group.

During the study period, the monkeys were observed at least once dailyfor signs of illness or distress. Any animal experiencing illness ordistress was promptly reported to the veterinarian and Study Director.Any animal in poor health or in a possible moribund condition wasidentified for further monitoring and possible euthanasia Scheduledeuthanasia of the animals was conducted on day 43 approximately 48 hoursafter the last dose by exsanguination while under deep anesthesia. Theprotocols described in the Example were approved by the InstitutionalAnimal Care and Use Committee (IACUC).

Body and Organ Weight Measurements

To evaluate the effect of modified oligonucleotides on the overallhealth of the animals, body and organ weights were measured. Terminalbody weight was measured prior to necropsy. Organ weights were measuredas well.

TABLE 22 Body and organ weights (g) Compound Body Weight No. (g) Day 43Heart kidney spleen liver Saline 2843 9 12 3 57 1304884 2643 9 14 4 651304890 2788 9 14 3 61 1304906 2678 10 13 3 60Kidney and Liver Function

To evaluate the effect of modified oligonucleotides on hepatic andkidney function, blood samples were collected from all the study groupson day 43. The monkeys were fasted overnight prior to blood collection.Blood was collected in tubes without anticoagulant for serum separation.The tubes were kept at room temperature for a minimum of 90 minutes andthen centrifuged at 3000 rpm for 10 minutes to obtain serum. Levels ofvarious liver function markers were measured using a Toshiba 120FR NEOchemistry analyzer (Toshiba Co., Japan). Plasma levels of blood ureanitrogen (BUN), creatinine (CREA), total protein (TP), alanineaminotransferase (ALT), aspartate aminotransferase (AST), and totalbilirubin (TBIL) were measured.

TABLE 23 Liver function markers in cynomolgus monkey plasma Compound ALTAST BUN CREA TP TBIL No. (IU/L) (IU/L) (mg/dL) (mg/dL) (g/dL) (mg/dL)Saline 52 74 28 1.0 7.0 0.3 1304884 64 47 23 0.9 7.0 0.2 1304890 52 6225 0.9 7.0 0.2 1304906 75 73 24 0.9 7.2 0.3Pro-Inflammatory Proteins Analysis

To evaluate any inflammatory effect of modified oligonucleotides incynomolgus monkeys, blood samples were taken for analysis. The monkeyswere fasted overnight prior to blood collection. On day 41 (pre-dose and24 hours post-dose), approximately 0.8 mL of blood was collected fromeach animal and put into tubes without anticoagulant for serumseparation. The tubes were kept at room temperature for a minimum of 90min and then centrifuged at 3,000 rpm for 10 min at room temperature toobtain serum. Complement C3 were measured using a Toshiba 120 FR NEOchemistry analyzer (Toshiba Co., Japan). Another marker of inflammation,C-Reactive Protein (CRP) was tested together with the clinical chemistryparameters tested for liver function above.

TABLE 24 Pro-inflammatory protein analysis in cynomolgus monkeysComplement C3 (mg/dL) CRP Compound Day 43 Day 43 (24 hr (mg/L) No.(pre-dose) post-dose) day 43 Saline 127 127 5 1304884 112 98 3 1304890102 98 3 1304906 108 88 3Hematology

To evaluate any effect of modified oligonucleotides in cynomolgusmonkeys on hematologic parameters, blood samples of approximately 0.5 mLof blood was collected from each of the available study animals on day43. The samples were collected in tubes containing K₂-EDTA. Samples wereanalyzed for red blood cell (RBC) count, Hemoglobin (HGB), Hematocrit(HCT), platelet count (PLT), total white blood cell count (WBC),neutrophil counts (NEU), lymphocyte counts (LYM), and monocyte counts(MON) using an ADVIA2120i hematology analyzer (Siemens, USA).

TABLE 25 Hematological marker analysis in cynomolgus monkeys CompoundRBC HGB HCT PLT WBC NEU LYM MON No. (×106/μL) (g/dL) (%) (10³/μL)(×10³/μL) (%) (%) (%) Saline 5 12 43 352 12 29 64 3 1304884 5 13 41 3869 30 62 3 1304890 5 13 42 460 12 33 62 2 1304906 6 13 42 413 13 48 46 4Urine Analysis

Food was removed overnight the day before fresh urine collection, butwater was supplied. Fresh urine samples for urinalysis and urinechemistry were collected from all animals using a clean cage pan on wetice (first in the morning) on day 43. Urinalysis/Urine Chemistryparameters creatinine (UCRE), microprotein (UTP), urine microalbumin(UALB), and protein/creatinine (P/C) ratio were measured using a Toshiba120FR automated chemistry analyzer (Toshiba Co., Japan).

TABLE 26 Urine analysis in cynomolgus monkeys Compound UCRE UTP UALB P/CNo. (mg/dL) (mg/dL) (mg/dL) ratio Saline 73 10 0.5 0.1 1304884 45 12 0.70.3 1304890 81 15 0.9 0.2 1304906 70 11 0.5 0.2

Example 11: Dose-Dependent Inhibition of Human MALAT1 in A431 Cells byComparator Compounds

Certain modified oligonucleotides described in the art were tested atvarious doses in A431 cells and used as comparator compounds in otherExamples below. The following modified oligonucleotides described in theart were compared: 395240, 395243, 395244, 395248, 395251, 395252,395253, 395254, 395255, 395256, 395257, 395259, 395267, 395269, 395272,395275, 395280, 395283, 395287, 395290, 556089, 559497, and 626112. Thechemical notation column in the table below specifies the sequence andchemistry information, including 5-methylcytosines, sugar chemistry, andthe internucleoside linkage chemistry; wherein subscript ‘d’ representsa 2′β-D-deoxyribosyl sugar moiety, subscript ‘k’ represents a cET sugarmoiety, subscript ‘e’ represents a 2′-MOE sugar moiety, subscript, ‘s’represents to a phosphorothioate internucleoside linkage, superscript‘m’ before the cytosine residue represents a 5-methylcytosine, andsubscript ‘o’ represents a phosphodiester internucleoside linkage.“Start site” indicates the 5′-most nucleoside to which the gapmer iscomplementary in the human nucleic acid sequence. “Stop site” indicatesthe 3′-most nucleoside to which the gapmer is complementary in the humannucleic acid sequence. Each modified oligonucleotide listed in the tablebelow is complementary to human MALAT1 nucleic acid sequence SEQ ID NO:1 (GENBANK Accession No: XR_001309.1).

TABLE 27 Certain Comparator Compounds SEQ SEQ ID ID NO: 1 NO: 1 SEQCompound Start Stop Sequence ID Number Site Site (5′ to 3′)Chemistry Notation (5′ to 3′) Reference Number No. 395240 3320 3339TGCCTTTAGG T_(es)G_(es) ^(m)C_(es)^(m)C_(es)T_(es)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds) WO 2012/012467 11ATTCTAGACA T_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(es)G_(es)A_(es)^(m)C_(es)A_(e) 395243 3885 3904 TAATTGCCAAT_(es)A_(es)A_(es)T_(es)T_(es)G_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(ds)T_(ds) WO 2012/012467 12 TATTTGCCCCA_(ds)T_(ds)T_(ds)T_(ds)G_(es) ^(m)C_(es) ^(m)C_(es) ^(m)C_(es)^(m)C_(e) 395244 4036 4055 GGGAGTTACTG_(es)G_(es)G_(es)A_(es)G_(es)T_(ds)T_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds)G_(ds) WO 2012/012467 13 TGCCAACTTG ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(es) ^(m)C_(es)T_(es)T_(es)G_(e) 395248 4493 4512TTGCAGTTAA T_(es)T_(es)G_(es)^(m)C_(es)A_(es)G_(ds)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds) WO 2012/012467 14ACAATGGAAA ^(m)C_(ds)A_(ds)A_(ds)T_(ds)G_(es)G_(es)A_(es)A_(es)A_(e)395251 4698 4717 CCAGGCTGGT ^(m)C_(es) ^(m)C_(es)A_(es)G_(es)G_(es)^(m)C_(ds)T_(ds)G_(ds)G_(ds)T_(ds)T_(ds) WO 2012/012467 15 TATGACTCAGA_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(es)T_(es) ^(m)C_(es)A_(es)G_(e) 3952524748 4767 TTATCAATTC T_(es)T_(es)A_(es)T_(es)^(m)C_(es)A_(ds)A_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ds) WO 2012/012467 16ACCAAGGAGC ^(m)C_(ds) ^(m)C_(ds)A_(ds)A_(ds)G_(es)G_(es)A_(es)G_(es)^(m)C_(e) 395253 4783 4802 ATGGAGGTATA_(es)T_(es)G_(es)G_(es)A_(es)G_(ds)G_(ds)T_(ds)A_(ds)T_(ds)G_(ds)A_(ds)WO 2012/012467 17 GACATATAAT^(m)C_(ds)A_(ds)T_(ds)A_(es)T_(es)A_(es)A_(es)T_(e) 395254 4843 4862GGCATATGCA G_(es)G_(es) ^(m)C_(es)A_(es)T_(es)A_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds)G_(ds) WO 2012/012467 18 GATAATGTTCA_(ds)T_(ds)A_(ds)A_(ds)T_(es)G_(es)T_(es)T_(es) ^(m)C_(e) 395255 51235142 ACATTGGCAC A_(es) ^(m)C_(es)A_(es)T_(es)T_(es)G_(ds)G_(ds)^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds) WO 2012/012467 19 ACAGCACAGC^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds)A_(es) ^(m)C_(es)A_(es)G_(es) ^(m)C_(e)395256 5134 5153 AGGCAAACGA A_(es)G_(es)G_(es)^(m)C_(es)A_(es)A_(ds)A_(ds) ^(m)C_(ds)G_(ds)A_(ds)A_(ds) WO 2012/01246720 AACATTGGCA A_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(es)G_(es)G_(es)^(m)C_(es)A_(e) 395257 5248 5267 CTAACATGCA ^(m)C_(es)T_(es)A_(es)A_(es)^(m)C_(es)A_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds) WO 2012/012467 21ATACTGCAGA T_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(es)^(m)C_(es)A_(es)G_(es)A_(e) 395259 5393 5412 AAGCCCACAGA_(es)A_(es)G_(es) ^(m)C_(es) ^(m)C_(es) ^(m)C_(ds)A_(ds)^(m)C_(ds)A_(ds)G_(ds) WO 2012/012467 22 GAACAAGTCC G_(ds)A_(ds)A_(ds)^(m)C_(ds)A_(ds)A_(es)G_(es)T_(es) ^(m)C_(es) ^(m)C_(e) 395267 6098 6117GGTCAATAGT G_(es)G_(es)T_(es)^(m)C_(es)A_(es)A_(ds)T_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)WO 2012/012467 23 GTAAAACATT A_(ds)A_(ds)A_(ds)A_(es)^(m)C_(es)A_(es)T_(es)T_(e) 395269 6174 6193 TTCATGAAGG T_(es)T_(es)^(m)C_(es)A_(es)T_(es)G_(ds)A_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)WO 2012/012467 24 ATGAAATGCC G_(ds)A_(ds)A_(ds)A_(es)T_(es)G_(es)^(m)C_(es) ^(m)C_(e) 395272 6445 6464 CAATGCATTC^(m)C_(es)A_(es)A_(es)T_(es)G_(es) ^(m)C_(ds)A_(ds)T_(ds)T_(ds)^(m)C_(ds)T_(ds) WO 2012/012467 25 TAATAGCAGCA_(ds)A_(ds)T_(ds)A_(ds)G_(es) ^(m)C_(es)A_(es)G_(es) ^(m)C_(e) 3952756759 6778 AACATTTCCA A_(es)A_(es) ^(m)C_(es)A_(es)T_(es)T_(ds)T_(ds)^(m)C_(ds) ^(m)C_(ds)A_(ds) WO 2012/012467 26 CTTGCCAGTT^(m)C_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)^(m)C_(es)A_(es)G_(es)T_(es)T_(e) 395280 6958 6977 GGTTCCCAATG_(es)G_(es)T_(es)T_(es) ^(m)C_(es) ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(ds)T_(ds) WO 2012/012467 27 CCCCACATTT ^(m)C_(ds)^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(es)A_(es)T_(es)T_(es)T_(e)395283 7335 7354 TAATAAAAATT_(es)A_(es)A_(es)T_(es)A_(es)A_(ds)A_(ds)A_(ds)A_(ds)T_(ds) ^(m)C_(ds)WO 2012/012467 28 CAGGTGAGGCA_(ds)G_(ds)G_(ds)T_(ds)G_(es)A_(es)G_(es)G_(es) ^(m)C_(e) 395287 78787897 TCCCACCCAG T_(es) ^(m)C_(es) ^(m)C_(es) ^(m)C_(es)A_(es) ^(m)C_(ds)^(m)C_(ds) ^(m)C_(ds)A_(ds)G_(ds) WO 2012/012467 29 CATTACAGTT^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(es)A_(es)G_(es)T_(es)T_(e)395290 8007 8026 TAAGATGCTA T_(es)A_(es)A_(es)G_(es)A_(es)T_(ds)G_(ds)^(m)C_(ds)T_(ds)A_(ds)G_(ds) WO 2012/012467 30 GCTTGGCCAA^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(es) ^(m)C_(es) ^(m)C_(es)A_(es)A_(e)556089 6445 6460 GCATTCTAAT G_(ks) ^(m)C_(ks)A_(ks)T_(ds)T_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds) WO 2017/192820; 31 AGCAGCG_(ds) ^(m)C_(ds)A_(ks)G_(ks) ^(m)C_(k) St-Pierre et al.,Bioorg Med Chem. 2016; 24(11): 2397-409 559497 3629 3644 AGTACTATAGA_(ks)G_(ks)T_(ks)A_(ds) ^(m)C_(ds)T_(ds)A_(ds)T_(ds)A_(ds)G_(ds)^(m)C_(ds) Hung et al., 32 CATCTG A_(ds)T_(ds) ^(m)C_(ks)T_(ks)G_(k)Nucleic Acid Ther. 2013; 23(6): 369-78. 626112 4699 4718 GCCAGGCTGGG_(es) ^(m)C_(eo) ^(m)C_(eo)A_(eo)G_(eo)G_(ds)^(m)C_(ds)T_(ds)G_(ds)G_(ds) WO 2016/073828 33 TTATGACTCAT_(ds)T_(ds)A_(ds)T_(ds)G_(ds)A_(eo) ^(m)C_(eo)T_(es) ^(m)C_(es)A_(e)

Compounds 1058667 and 1058668 have been described in the art. Thechemical notation column in the table below specifies the sequence andchemistry information of certain comparator compounds, including5-methylcytosines, sugar chemistry, and the internucleoside linkagechemistry; wherein subscript ‘d’ represents a 2′β-D-deoxyribosyl sugarmoiety, subscript ‘1’ represents an LNA sugar moiety, subscript ‘s’represents to a phosphorothioate internucleoside linkage, andsuperscript ‘m’ before the cytosine residue represents a5-methylcytosine. Compounds 1058667 and 1058668 are complementary tomouse MALAT1 nucleic acid sequence and mismatched with human MALAT1nucleic acid sequence. “Start site” indicates the 5′-most nucleoside towhich the gapmer is complementary in the mouse nucleic acid sequence.“Stop site” indicates the 3′-most nucleoside to which the gapmer iscomplementary in the mouse nucleic acid sequence. Each modifiedoligonucleotide listed in the table below is complementary to mouseMALAT1 nucleic acid sequence SEQ ID NO: 2823 (complement of GENBANKAccession No: NC_000085.6 truncated from nucleotides 5793001 to 5806000)

TABLE 28 Certain Comparator Compounds SEQ SEQ ID ID NO: NO: 2823 2823SEQ Compound Start Stop Sequence Chemistry Notation ID Number Site Site(5′ to 3′) (5′ to 3′) Reference Number No. 1058668 8368 8383 GTCACAATG_(ls)T_(ls) ^(m)C_(ls)A_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)Michalik et al., 34 GCATTCTA G_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ds)^(m)C_(ls)T_(ls)A_(l) Circ Res. 2014; 114(9): 1389-97 and WO 2019/1613641058667 6043 6061 TTTAAGTTT_(ls)T_(ls)T_(ls)A_(ds)A_(ds)G_(ds)T_(ds)T_(ds) Bernard et al. 35CTCTGGTA ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds)G_(ds)T_(ds)A_(ds)EMBO J 2010 TGA T_(ls)G_(ls)A_(l) 29(18): 3082-93

The modified oligonucleotides below were tested in a series ofexperiments using the same culture conditions. The results for eachexperiment are presented in separate tables shown below. Cultured A431cells at a density of 10,000 cells per well were transfected using freeuptake with modified oligonucleotides diluted to differentconcentrations as specified in the tables below. After a treatmentperiod of approximately 48 hours, RNA levels were measured as previouslydescribed using the Human primer-probe set RTS2738 (described hereinabove). MALAT1 RNA levels were normalized to total RNA, as measured byRIBOGREEN®. Results are presented as percent change of MALAT1 RNA,relative to PBS control.

The half maximal inhibitory concentration (IC₅₀) of each modifiedoligonucleotide was calculated using a linear regression on a log/linearplot of the data in excel and is also presented in the tables below.

TABLE 29 Dose-dependent percent reduction of human MALAT1 RNA in A431cells by modified oligonucleotides Compound MALAT1 (% UTC) Number 0.4 nM2 nM 10 nM 50 nM 250 nM IC₅₀ nM 395240 98 72 37 10 4 7 395243 97 101 10148 10 46 395244 91 84 58 12 7 10 395248 92 97 49 20 6 12 395255 126 12188 35 13 39 395256 111 108 77 19 4 21 395257 80 94 74 40 16 26 395259121 97 101 52 23 68 395280 103 115 73 32 14 29 395283 107 89 84 25 10 23395287 93 78 63 51 31 41 395290 113 90 101 34 18 40 626112 92 93 76 3414 24

TABLE 30 Dose-dependent percent reduction of human MALAT1 RNA in A431cells by modified oligonucleotides Compound MALAT1 (% UTC) Number 0.4 nM2 nM 10 nM 50 nM 250 nM IC₅₀ nM  395251 103 88 54 11 4 11  395252 100117 68 22 6 20  395253 110 87 73 14 4 15  395254 106 73 32 10 5 7 395267 143 126 71 22 6 27  395269 97 112 123 61 26 168  395272 89 87 7868 19 63  395275 83 81 69 29 14 16  556089 106 107 79 37 11 30  55949788 102 59 23 6 14 1058667 131 118 99 30 11 39 1058668 105 95 74 27 7 20

Example 12: Antisense Inhibition of Human MALAT1 in A431 Cells by 3-10-3cEt Gapmers

Modified oligonucleotides complementary to a MALAT1 nucleic acid weresynthesized and tested for their effect on MALAT1 RNA levels in vitro incomparison with comparator compounds 395240, 395253, 395254, 395256,556089, and 559497 described above. The modified oligonucleotides weretested in a series of experiments using the same culture conditions. Theresults for each separate experiment are presented in separate tablesbelow.

Except for the comparator compounds 395240, 395253, 395254, and 395256,which are 5-10-5 MOE gapmers (i.e., they have a central gap segment often 2′-deoxynucleosides flanked on each side by wing segments, eachcomprising five 2′-O-methoxyethyl modified nucleosides), the modifiedoligonucleotides are all 3-10-3 cEt gapmers (i.e., they have a centralgap segment of ten 2′-deoxynucleosides flanked on each side by wingsegments, each comprising three cEt modified nucleosides). Theinternucleoside linkages throughout each modified oligonucleotide arephosphorothioate (P═S) linkages. All cytosine nucleobases throughouteach modified oligonucleotide are 5-methylcytosines.

“Start site” indicates the 5′-most nucleoside of the target sequence towhich the modified oligonucleotide is complementary. “Stop site”indicates the 3′-most nucleoside of the target sequence to which themodified oligonucleotide is complementary. As shown in the tables below,the modified oligonucleotides are 100% complementary to either the humanMALAT1 RNA transcript, designated herein as SEQ ID NO: 1 (GENBANKAccession No. XR_001309.1) or the human MALAT1 RNA transcript designatedhere in as SEQ ID NO: 2824 (GENBANK Accession No. EF177381.1). ‘N/A’indicates that the modified oligonucleotide is not complementary to thatparticular target sequence with 100% complementarity.

Cultured A431 cells at a density of 10,000 cells per well weretransfected using free uptake with 5 nM of modified oligonucleotide.After a treatment period of 48 hours, RNA was isolated from the cellsand MALAT1 RNA levels were measured by quantitative real-time RTPCR.Human MALAT1 primer probe set RTS2736 (described herein above) was usedto measure RNA levels. MALAT1 RNA levels were normalized to total RNAcontent, as measured by RIBOGREEN®. Results are presented as percentchange of MALAT1 RNA, relative to PBS control (% UTC). The symbol “‡”indicates that the modified oligonucleotide is complementary to thetarget transcript within the amplicon region of the primer probe set,and so the associated data is not reliable. In such instances,additional assays using alternative primer probes must be performed toaccurately assess the potency and efficacy of such modifiedoligonucleotides. In some cases, % UTC values are not available. This isindicated as N.D. (Not Defined) and additional assays will be performedto accurately assess the potency and efficacy of such modifiedoligonucleotides.

Modified oligonucleotides marked with a triple asterisk (

) have been previously described in Example 1. The % UTC data formodified oligonucleotides marked with a triple asterisk (

) in the tables below is identical to the data described in Example 2 asthe data is from the same experiments.

TABLE 31 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: NO: NO: 1 NO: 1 2824 2824 SEQ Compound Start StopStart Stop MALAT1 ID Number Site Site Site Site Sequence (5′ to 3′)(% UTC) No.  395240 3320 3339 3520 3539 TGCCTTTAGGATTCTAGACA  61  11 395253 4783 4802 4982 5001 ATGGAGGTATGACATATAAT  78  17  395254 48434862 5042 5061 GGCATATGCAGATAATGTTC  61  18  395256 5134 5153 5333 5352AGGCAAACGAAACATTGGCA  97  20  556089 6445 6460 6644 6659GCATTCTAATAGCAGC  90  31  559497 3629 3644 3829 3844 AGTACTATAGCATCTG124  32  559564 2839 2854 3039 3054 CCATAAGTAAGTTCCA  42  36 1156449  11   26 N/A N/A CGGGCTGCAGGCTGCG  86  37 1156482  157  172  123  138ACCTGGGCTCCCGGAG  81  38 1156515  252  267  218  233 GGTTTTATCTAAATAC 75  39 1156549  348  363  314  329 CCTGGTTAGGTATGAG  81  40 1156583 483  498  449  464 GACCAACTAAGCGAAT  61  41 1156617  529  544  495  510AAGGCAAATCGCCATG  86  42 1156651  598  613  564  579 GCCCCCCACGGCCCGC 90  43 1156685  720  735  686  701 CGTGAAAACCCACTCT 106  44 1156718 829  844  795  810 CCCCAACTGCTTGCAG  87  45 1156752  892  907  858  873TTACGCAACTGAGCCC  89  46 1156786  957  972  923  938 GTAGGTATAGTTTACC 61  47 1156820 N/A N/A 1006 1021 AAACGGGTCATCAAAC  81  48 1156854 N/AN/A 1119 1134 ACAGCTTATGGAACTT  73  49 1156888 1015 1030 1215 1230GGAATTCGATCACCTT  71  50 1156922 1068 1083 1268 1283 ACCGCACAGCTCGGGC 95  51 1156956 1172 1187 1372 1387 TGTATTAATCTCTATC  59  52 11569901331 1346 1531 1546 ACCTCCGTCATGTTTT  57  53 1157023 1513 1528 1713 1728AGATCGCCTTCAAATT  59  54 1157057 1588 1603 1788 1803 TTTAAATGACGCAATT 85  55 1157090 1846 1861 2046 2061 TGCCCTTAGCTTTTTG  44  56 11571242094 2109 2294 2309 GCTTTACCTTCTAACT  31  57 1157158 2278 2293 2478 2493GCTACTATATTTAAGG  71  58 1157190 

2341 2356 2541 2556 TGGTAATTACTCTTGA  19   4 1157224 2434 2449 2634 2649TCTGTGTAGCACCTGG  37  59 1157258 2546 2561 2746 2761 TATCTTCACCACGAAC100  60 1157292 2671 2686 2871 2886 CATCACCAAATTGCAC  72  61 11573252744 2759 2944 2959 GTCTAGGATCCTCTAC  86  62 1157359 2814 2829 3014 3029CATATTGCCGACCTCA  57  63 1157393 2893 2908 3093 3108 TTTACACCTCAGTACG 65  64 1157426 2971 2986 3171 3186 ACAAGATTCATGAGTA  73  65 11574583122 3137 3322 3337 CATACAAACTGCTTAC  71  66 1157492 3234 3249 3434 3449CCCCGCCTCAGTTACA  65  67 1157525 3335 3350 3535 3550 CTTGAGTCATTTGCCT 35  68 1157559 3447 3462 3647 3662 ATGGACATCTCTTCCA  70  69 11575913628 3643 3828 3843 GTACTATAGCATCTGT  55  70 1157624 3697 3712 3897 3912TCCAGTCCCTGAAGGT  88  71 1157658 3824 3839 4024 4039 AACTTCAACATTTGGC 44  72 1157691 3941 3956 4141 4156 CAATTACCTAAACCCA  80  73 11577254050 4065 4250 4265 CTAAATCATTGGGAGT  52  74 1157758 4184 4199 4384 4399GCTCTATACTTTGAAG  49  75 1157791 4274 4289 4474 4489 CCAAACAACTTTTGCA 56  76 1157825 4428 4443 4628 4643 TAGAATCTTACTTGAT  66  77 11578584614 4629 4813 4828 CCTCTAAGAGACATTC  71  78 1157890 4747 4762 4946 4961AATTCACCAAGGAGCT  65  79 1157924 4815 4830 5014 5029 AGAATCTCAGGGTTAT 36  80 1157958 4903 4918 5102 5117 AAAATGGTAGATTCCG  19  81 11579925050 5065 5249 5264 AGGATTAATGTAGTGT  13  82 1158025 5137 5152 5336 5351GGCAAACGAAACATTG  65  83 1158058 5220 5235 5419 5434 TTATCTGTTAACAGCT 69  84 1158091 5286 5301 5485 5500 GAACTCCACAGCTCTT  67  85 11581235388 5403 5587 5602 GGAACAAGTCCTACAA  77  86 1158156 5487 5502 5686 5701TGGCATCAAGGCACTG  51  87 1158190 5577 5592 5776 5791 TTTTAGCAGTAACATC 66  88 1158223 5773 5788 5972 5987 AGTGTTCGCAGACAAA  66  89 11582565896 5911 6095 6110 GCCTCTATTGCCATGT  70  90 1158289 5993 6008 6192 6207AGACCCCTGACTTTCT  78  91 1158323 6081 6096 6280 6295 CCTACCACTCTAAGAT 73  92 1158357 6195 6210 6394 6409 TCAAAATCCTGAATGG  62  93 11583906324 6339 6523 6538 AGTAAGCCCCACCCCC  71  94 1158423 6436 6451 6635 6650TAGCAGCGGGATCAGA  68  95 1158455 6537 6552 6736 6751 CTTTATCACTCAGCTG 63  96 1158488 6695 6710 6894 6909 TTTAAGGTTGCATCTG  59  97 11585196968 6983 7167 7182 ACTAGTGGTTCCCAAT  67  98 1158552 7062 7077 7261 7276CAGAAAAAGCTTGTTC  63  99 1158586 7159 7174 7358 7373 GCCAACACAGTTTGCT 70 100 1158618 7306 7321 7505 7520 GACCTTAGGATAATAG  20 101 11586527399 7414 7598 7613 TCAAGCATTCCTTCGG  27 102 1158685 7522 7537 7721 7736AAAAGTGGTTGCCCGC  72 103 1158719 7654 7669 7853 7868 TCCAAGCTACTGGCTG 80 104 1158753 7708 7723 7907 7922 AGACCTCGACACCATC  54 105 11587857775 7790 7974 7989 TAATACCCTTCTGTTA  81 106 1158819 7872 7887 8071 8086CATTACAGTTCTTGAA  59 107 1158852 7949 7964 8148 8163 GCATTCCCACCCAAAA 66 108 1158885 8040 8055 8239 8254 ACTGAAGAGCATTGGA  66 109 11589168196 8211 8395 8410 CGCCGCAGGGATTTGA  81 110 1158950 8328 8343 8527 8542CAAGGATGTATATAGT 100 111 1158984‡ 8424 8439 8623 8638 CTGCAGGCTATTACCT106 112

TABLE 32 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: NO: NO: 1 NO: 1 2824 2824 SEQ Compound Start StopStart Stop MALAT1 ID Number Site Site Site Site Sequence (5′ to 3′)(% UTC) No.  395240 3320 3339 3520 3539 TGCCTTTAGGATTCTAGACA  49  11 395253 4783 4802 4982 5001 ATGGAGGTATGACATATAAT  75  17  395254 48434862 5042 5061 GGCATATGCAGATAATGTTC  49  18  395256 5134 5153 5333 5352AGGCAAACGAAACATTGGCA  88  20  556089 6445 6460 6644 6659GCATTCTAATAGCAGC  79  31  559497 3629 3644 3829 3844 AGTACTATAGCATCTG117  32  559564 2839 2854 3039 3054 CCATAAGTAAGTTCCA  27  36  9464176325 6340 6524 6539 AAGTAAGCCCCACCCC  63 113  946420 7160 7175 7359 7374CGCCAACACAGTTTGC  88 114 1156450   13   28 N/A N/A CTCGGGCTGCAGGCTG  81115 1156483  158  173  124  139 AACCTGGGCTCCCGGA  70 116 1156516  256 271  222  237 GAGTGGTTTTATCTAA  69 117 1156550  349  364  315  330GCCTGGTTAGGTATGA  79 118 1156584  484  499  450  465 AGACCAACTAAGCGAA 62 119 1156618  530  545  496  511 CAAGGCAAATCGCCAT  58 120 1156652 599  614  565  580 AGCCCCCCACGGCCCG  73 121 1156686  734  749  700  715GGAAATCTTAGAAACG  64 122 1156719  830  845  796  811 CCCCCAACTGCTTGCA 71 123 1156753  893  908  859  874 ATTACGCAACTGAGCC  84 124 1156787 958  973  924  939 AGTAGGTATAGTTTAC  90 125 1156821 N/A N/A 1007 1022TAAACGGGTCATCAAA  66 126 1156855 N/A N/A 1123 1138 CTTAACAGCTTATGGA  70127 1156889 1016 1031 1216 1231 CGGAATTCGATCACCT  81 128 1156923 10691084 1269 1284 TACCGCACAGCTCGGG  80 129 1156957 1174 1189 1374 1389GTTGTATTAATCTCTA  24 130 1156991 1333 1348 1533 1548 CAACCTCCGTCATGTT 65 131 1157024 1514 1529 1714 1729 AAGATCGCCTTCAAAT  51 132 11570581589 1604 1789 1804 CTTTAAATGACGCAAT  65 133 1157091 1851 1866 2051 2066CATTTTGCCCTTAGCT  46 134 1157125 2095 2110 2295 2310 AGCTTTACCTTCTAAC 53 135 1157159 2283 2298 2483 2498 ACTAAGCTACTATATT  61 136 11571912342 2357 2542 2557 TTGGTAATTACTCTTG  32 137 1157225 2441 2456 2641 2656ATCCACTTCTGTGTAG  62 138 1157259 2547 2562 2747 2762 CTATCTTCACCACGAA 60 139 1157293 2676 2691 2876 2891 ACCTTCATCACCAAAT  78 140 11573262745 2760 2945 2960 GGTCTAGGATCCTCTA  77 141 1157360 2815 2830 3015 3030ACATATTGCCGACCTC  57 142 1157394 2894 2909 3094 3109 CTTTACACCTCAGTAC 62 143 1157427 2972 2987 3172 3187 GACAAGATTCATGAGT  53 144 11574593133 3148 3333 3348 CCCCAACTAAACATAC  74 145 1157493 3235 3250 3435 3450CCCCCGCCTCAGTTAC  72 146 1157526 3337 3352 3537 3552 ACCTTGAGTCATTTGC 34 147 1157560 3448 3463 3648 3663 AATGGACATCTCTTCC  73 148 11575923630 3645 3830 3845 TAGTACTATAGCATCT  51 149 1157625 3709 3724 3909 3924GATAAAAGCAGCTCCA  70 150 1157659 3837 3852 4037 4052 TATTGGAAAACTTAAC 74 151 1157692 3942 3957 4142 4157 ACAATTACCTAAACCC  67 152 11577264051 4066 4251 4266 ACTAAATCATTGGGAG  41 153 1157759 4185 4200 4385 4400AGCTCTATACTTTGAA  36 154 1157792 4282 4297 4482 4497 TACCATATCCAAACAA 89 155 1157826 4429 4444 4629 4644 ATAGAATCTTACTTGA  34 156 11578594615 4630 4814 4829 CCCTCTAAGAGACATT  68 157 1157891 4751 4766 4950 4965TATCAATTCACCAAGG  99 158 1157925 4817 4832 5016 5031 TAAGAATCTCAGGGTT 31 159 1157959 4904 4919 5103 5118 TAAAATGGTAGATTCC  12 160 11579935051 5066 5250 5265 CAGGATTAATGTAGTG  15 161 1158026 5138 5153 5337 5352AGGCAAACGAAACATT  65 162 1158059 5221 5236 5420 5435 CTTATCTGTTAACAGC 57 163 1158092 5289 5304 5488 5503 TAAGAACTCCACAGCT  59 164 11581245389 5404 5588 5603 AGGAACAAGTCCTACA  64 165 1158157 5488 5503 5687 5702TTGGCATCAAGGCACT  28 166 1158191 5600 5615 5799 5814 CAATTTACATCACAAC 55 167 1158224 5775 5790 5974 5989 AGAGTGTTCGCAGACA  43 168 11582575900 5915 6099 6114 GAGGGCCTCTATTGCC  86 169 1158290 5995 6010 6194 6209ATAGACCCCTGACTTT  66 170 1158324 6082 6097 6281 6296 GCCTACCACTCTAAGA 71 171 1158358 6200 6215 6399 6414 GCAATTCAAAATCCTG  49 172 11584246437 6452 6636 6651 ATAGCAGCGGGATCAG  43 173 1158456 6538 6553 6737 6752CCTTTATCACTCAGCT  46 174 1158489 6697 6712 6896 6911 ATTTTAAGGTTGCATC 63 175 1158520 6970 6985 7169 7184 GAACTAGTGGTTCCCA  54 176 11585537081 7096 7280 7295 CTGACTTTGTATGTAA  49 177 1158619 7307 7322 7506 7521TGACCTTAGGATAATA  38 178 1158653 7400 7415 7599 7614 TTCAAGCATTCCTTCG 38 179 1158686 7523 7538 7722 7737 GAAAAGTGGTTGCCCG  68 180 11587207655 7670 7854 7869 ATCCAAGCTACTGGCT  60 181 1158754 7709 7724 7908 7923AAGACCTCGACACCAT  56 182 1158786 7780 7795 7979 7994 GGTTTTAATACCCTTC 49 183 1158820 7873 7888 8072 8087 GCATTACAGTTCTTGA  28 184 11588537968 7983 8167 8182 GTCTTAGCAGAGAATT  53 185 1158886 8041 8056 8240 8255TACTGAAGAGCATTGG  29 186 1158917 8210 8225 8409 8424 AGTCAAAGCAAAGACG 65 187 1158951 8329 8344 8528 8543 TCAAGGATGTATATAG  94 188 11589858426 8441 8625 8640 AGCTGCAGGCTATTAC  61 189

Example 13: Antisense Inhibition of Human MALAT1 in A431 Cells by 3-10-3cEt Gapmers

Modified oligonucleotides complementary to a MALAT1 nucleic acid weresynthesized and tested for their effect on MALAT1 RNA levels in vitro incomparison with comparator compounds 395254 and 559497 described above.The modified oligonucleotides were tested in a series of experimentsusing the same culture conditions. The results for each separateexperiment are presented in separate tables below.

Except for the comparator compound 395254, which is a 5-10-5 MOE gapmer(i.e., it has a central gap segment of ten 2′-deoxynucleosides flankedon each side by wing segments, each comprising five 2′-O-methoxyethylmodified nucleosides), the modified oligonucleotides are all 3-10-3 cEtgapmers (i.e., they have a central gap segment of ten2′-deoxynucleosides flanked on each side by wing segments, eachcomprising three cEt modified nucleosides). The internucleoside linkagesthroughout each modified oligonucleotide are phosphorothioate (P═S)linkages. All cytosine nucleobases throughout each modifiedoligonucleotide are 5-methylcytosines.

“Start site” indicates the 5′-most nucleoside of the target sequence towhich the modified oligonucleotide is complementary. “Stop site”indicates the 3′-most nucleoside of the target sequence to which themodified oligonucleotide is complementary. As shown in the tables below,the modified oligonucleotides are 100% complementary to either the humanMALAT1 RNA transcript, designated herein as SEQ ID NO: 1 (GENBANKAccession No. XR_001309.1) or the human MALAT1 RNA transcript designatedhere in as SEQ ID NO: 2824 (GENBANK Accession No. EF177381.1). ‘N/A’indicates that the modified oligonucleotide is not complementary to thatparticular target sequence with 100% complementarity.

TABLE 33 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: NO: NO: 1 NO: 1 2824 2824 SEQ Compound Start StopStart Stop MALAT1 ID Number Site Site Site Site Sequence (5′ to 3′)(% UTC) No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC 107  18 559497 3629 3644 3829 3844 AGTACTATAGCATCTG 130  32  559564 2839 28543039 3054 CCATAAGTAAGTTCCA  38  36  568439 1590 1605 1790 1805GCTTTAAATGACGCAA 122 190 1156451   14   29 N/A N/A TCTCGGGCTGCAGGCT  80191 1156484  159  174  125  140 AAACCTGGGCTCCCGG  80 192 1156517  257 272  223  238 TGAGTGGTTTTATCTA  93 193 1156551  354  369  320  335GTTATGCCTGGTTAGG  84 194 1156585  485  500  451  466 TAGACCAACTAAGCGA109 195 1156619  531  546  497  512 ACAAGGCAAATCGCCA  83 196 1156653 603  618  569  584 CGCCAGCCCCCCACGG 145 197 1156687  738  753  704  719CTTGGGAAATCTTAGA 111 198 1156720  831  846  797  812 TCCCCCAACTGCTTGC 89 199 1156754  894  909  860  875 CATTACGCAACTGAGC 101 200 1156788 959  974  925  940 CAGTAGGTATAGTTTA 117 201 1156822 N/A N/A 1008 1023TTAAACGGGTCATCAA 100 202 1156856 N/A N/A 1124 1139 TCTTAACAGCTTATGG  69203 1156890 1017 1032 1217 1232 CCGGAATTCGATCACC  91 204 1156924 10711086 1271 1286 CCTACCGCACAGCTCG  97 205 1156958 1176 1191 1376 1391TAGTTGTATTAATCTC  62 206 1156992 1334 1349 1534 1549 TCAACCTCCGTCATGT 68 207 1157025 1515 1530 1715 1730 AAAGATCGCCTTCAAA  68 208 11570921853 1868 2053 2068 TACATTTTGCCCTTAG  30 209 1157126 2117 2132 2317 2332CGTAAACACCCTCATC  68 210 1157160 2284 2299 2484 2499 AACTAAGCTACTATAT102 211 1157192 2344 2359 2544 2559 AGTTGGTAATTACTCT  60 212 11572262446 2461 2646 2661 ACTGAATCCACTTCTG  65 213 1157260 2548 2563 2748 2763CCTATCTTCACCACGA  94 214 1157294 2678 2693 2878 2893 CTACCTTCATCACCAA 98 215 1157327 2746 2761 2946 2961 TGGTCTAGGATCCTCT 115 216 11573612816 2831 3016 3031 AACATATTGCCGACCT  55 217 1157395 2895 2910 3095 3110CCTTTACACCTCAGTA  87 218 1157428 2973 2988 3173 3188 AGACAAGATTCATGAG 50 219 1157460 3134 3149 3334 3349 ACCCCAACTAAACATA  74 220 11574943236 3251 3436 3451 CCCCCCGCCTCAGTTA 107 221 1157527 3338 3353 3538 3553CACCTTGAGTCATTTG  63 222 1157561 3449 3464 3649 3664 CAATGGACATCTCTTC 51 223 1157593 3631 3646 3831 3846 ATAGTACTATAGCATC  70 224 11576263710 3725 3910 3925 GGATAAAAGCAGCTCC  68 225 1157660 3872 3887 4072 4087CCCTCCCCTTTAATAA 117 226 1157693 3943 3958 4143 4158 AACAATTACCTAAACC 84 227 1157727 4052 4067 4252 4267 AACTAAATCATTGGGA 101 228 11577604190 4205 4390 4405 CCAAAAGCTCTATACT  88 229 1157793 4283 4298 4483 4498CTACCATATCCAAACA  79 230 1157827 4447 4462 4647 4662 GCTTACACACAACTGA 50 231 1157860 4616 4631 4815 4830 ACCCTCTAAGAGACAT  65 232 11578924752 4767 4951 4966 TTATCAATTCACCAAG  75 233 1157926 4818 4833 5017 5032GTAAGAATCTCAGGGT  22 234 1157960 4920 4935 5119 5134 GACAAGCAATTAACTT 34 235 1157994 5052 5067 5251 5266 CCAGGATTAATGTAGT  29 236 11580275139 5154 5338 5353 GAGGCAAACGAAACAT  99 237 1158060 5222 5237 5421 5436ACTTATCTGTTAACAG  75 238 1158093 5290 5305 5489 5504 TTAAGAACTCCACAGC 54 239 1158125 5390 5405 5589 5604 CAGGAACAAGTCCTAC  81 240 11581585491 5506 5690 5705 TAGTTGGCATCAAGGC  28 241 1158192 5605 5620 5804 5819CTACACAATTTACATC  78 242 1158225 5777 5792 5976 5991 AAAGAGTGTTCGCAGA 46 243 1158258 5901 5916 6100 6115 AGAGGGCCTCTATTGC  67 244 11582915996 6011 6195 6210 TATAGACCCCTGACTT  58 245 1158325 6083 6098 6282 6297TGCCTACCACTCTAAG 110 246 1158359 6208 6223 6407 6422 ACTCATATGCAATTCA 39 247 1158391 6326 6341 6525 6540 CAAGTAAGCCCCACCC  74 248 11584256438 6453 6637 6652 AATAGCAGCGGGATCA  66 249 1158457 6539 6554 6738 6753GCCTTTATCACTCAGC  71 250 1158490 6698 6713 6897 6912 GATTTTAAGGTTGCAT 45 251 1158521 6971 6986 7170 7185 AGAACTAGTGGTTCCC 103 252 11585547082 7097 7281 7296 TCTGACTTTGTATGTA  52 253 1158587 7161 7176 7360 7375ACGCCAACACAGTTTG  52 254 1158620 7308 7323 7507 7522 TTGACCTTAGGATAAT 53 255 1158654 7405 7420 7604 7619 GGTACTTCAAGCATTC  56 256 11586877524 7539 7723 7738 GGAAAAGTGGTTGCCC  76 257 1158721 7656 7671 7855 7870GATCCAAGCTACTGGC  82 258 1158755 7710 7725 7909 7924 AAAGACCTCGACACCA 85 259 1158787 7781 7796 7980 7995 TGGTTTTAATACCCTT  89 260 11588217874 7889 8073 8088 AGCATTACAGTTCTTG  22 261 1158854 7977 7992 8176 8191CCTGAAAAAGTCTTAG  72 262 1158887 8042 8057 8241 8256 CTACTGAAGAGCATTG 78 263 1158918 8216 8231 8415 8430 ATTAGTAGTCAAAGCA  80 264 11589528330 8345 8529 8544 ATCAAGGATGTATATA 100 265 1158986 8445 8460 8644 8659TAGGGCTTCTCAAAAC  96 266

TABLE 34 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: NO: NO: 1 NO: 1 2824 2824 SEQ Compound Start StopStart Stop MALAT1 ID Number Site Site Site Site Sequence (5′ to 3′)(% UTC) No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC  96  18 556064 5140 5155 5339 5354 TGAGGCAAACGAAACA  84 267  559497 3629 36443829 3844 AGTACTATAGCATCTG 123  32  559564 2839 2854 3039 3054CCATAAGTAAGTTCCA  33  36 1156452   15   30 N/A N/A GTCTCGGGCTGCAGGC 106268 1156485  160  175  126  141 GAAACCTGGGCTCCCG  87 269 1156518  262 277  228  243 GAGTTTGAGTGGTTTT  74 270 1156552  356  371  322  337GTGTTATGCCTGGTTA  98 271 1156586  486  501  452  467 GTAGACCAACTAAGCG 74 272 1156620  532  547  498  513 CACAAGGCAAATCGCC  80 273 1156654 610  625  576  591 CAGTTGCCGCCAGCCC 103 274 1156688  739  754  705  720GCTTGGGAAATCTTAG  93 275 1156721  832  847  798  813 CTCCCCCAACTGCTTG 78 276 1156755  895  910  861  876 CCATTACGCAACTGAG  88 277 1156789 960  975  926  941 ACAGTAGGTATAGTTT  76 278 1156823 N/A N/A 1009 1024TTTAAACGGGTCATCA  90 279 1156857 N/A N/A 1125 1140 TTCTTAACAGCTTATG  79280 1156891 1018 1033 1218 1233 ACCGGAATTCGATCAC  65 281 1156925 10721087 1272 1287 GCCTACCGCACAGCTC  74 282 1156959 1177 1192 1377 1392GTAGTTGTATTAATCT  32 283 1156993 1335 1350 1535 1550 CTCAACCTCCGTCATG 41 284 1157026 1516 1531 1716 1731 AAAAGATCGCCTTCAA  66 285 11570591591 1606 1791 1806 GGCTTTAAATGACGCA  83 286 1157093 1854 1869 2054 2069GTACATTTTGCCCTTA  36 287 1157127 2133 2148 2333 2348 AATTGGTTCTGGTCTA 42 288 1157161 2285 2300 2485 2500 AAACTAAGCTACTATA 117 289 11571932345 2360 2545 2560 AAGTTGGTAATTACTC  78 290 1157227 2451 2466 2651 2666GATTCACTGAATCCAC  92 291 1157261 2549 2564 2749 2764 TCCTATCTTCACCACG 60 292 1157295 2681 2696 2881 2896 CTGCTACCTTCATCAC  61 293 11573282755 2770 2955 2970 CTGGCATGCTGGTCTA  81 294 1157362 2817 2832 3017 3032CAACATATTGCCGACC 126 295 1157396 2896 2911 3096 3111 CCCTTTACACCTCAGT 75 296 1157429 2974 2989 3174 3189 CAGACAAGATTCATGA  81 297 11574613135 3150 3335 3350 TACCCCAACTAAACAT  82 298 1157495 3237 3252 3437 3452CCCCCCCGCCTCAGTT  85 299 1157528 3339 3354 3539 3554 ACACCTTGAGTCATTT 50 300 1157562 3450 3465 3650 3665 CCAATGGACATCTCTT  60 301 11575943632 3647 3832 3847 AATAGTACTATAGCAT  85 302 1157627 3722 3737 3922 3937ATACTCTTCCAAGGAT  65 303 1157661 3876 3891 4076 4091 TTGCCCCTCCCCTTTA 58 304 1157694 3946 3961 4146 4161 CTAAACAATTACCTAA  97 305 11577284053 4068 4253 4268 AAACTAAATCATTGGG  57 306 1157761 4191 4206 4391 4406CCCAAAAGCTCTATAC  94 307 1157794 4284 4299 4484 4499 ACTACCATATCCAAAC 73 308 1157828 4448 4463 4648 4663 TGCTTACACACAACTG  65 309 11578614617 4632 4816 4831 CACCCTCTAAGAGACA  99 310 1157893 4753 4768 4952 4967CTTATCAATTCACCAA  53 311 1157927 4819 4834 5018 5033 AGTAAGAATCTCAGGG 55 312 1157961 4921 4936 5120 5135 TGACAAGCAATTAACT  72 313 11579955053 5068 5252 5267 TCCAGGATTAATGTAG  52 314 1158061 5223 5238 5422 5437AACTTATCTGTTAACA  70 315 1158094 5293 5308 5492 5507 TATTTAAGAACTCCAC 74 316 1158126 5391 5406 5590 5605 ACAGGAACAAGTCCTA  90 317 11581595492 5507 5691 5706 TTAGTTGGCATCAAGG  26 318 1158193 5615 5630 5814 5829TAATGGTTTTCTACAC  60 319 1158226 5778 5793 5977 5992 TAAAGAGTGTTCGCAG 49 320 1158259 5902 5917 6101 6116 TAGAGGGCCTCTATTG  61 321 11582925997 6012 6196 6211 TTATAGACCCCTGACT  90 322 1158326 6084 6099 6283 6298TTGCCTACCACTCTAA 100 323 1158360 6209 6224 6408 6423 CACTCATATGCAATTC 63 324 1158392 6328 6343 6527 6542 AACAAGTAAGCCCCAC  89 325 11584266439 6454 6638 6653 TAATAGCAGCGGGATC  70 326 1158458 6540 6555 6739 6754AGCCTTTATCACTCAG  65 327 1158491 6699 6714 6898 6913 TGATTTTAAGGTTGCA 30 328 1158522 6972 6987 7171 7186 AAGAACTAGTGGTTCC  70 329 11585557085 7100 7284 7299 TGATCTGACTTTGTAT  53 330 1158588 7162 7177 7361 7376CACGCCAACACAGTTT  64 331 1158621 7309 7324 7508 7523 CTTGACCTTAGGATAA 56 332 1158655 7406 7421 7605 7620 GGGTACTTCAAGCATT  57 333 11586887525 7540 7724 7739 GGGAAAAGTGGTTGCC  91 334 1158722 7657 7672 7856 7871GGATCCAAGCTACTGG  82 335 1158756 7711 7726 7910 7925 CAAAGACCTCGACACC 82 336 1158788 7784 7799 7983 7998 CTGTGGTTTTAATACC  49 337 11588227876 7891 8075 8090 CCAGCATTACAGTTCT  58 338 1158855 7987 8002 8186 8201GTTATGTTCACCTGAA  39 339 1158888 8043 8058 8242 8257 CCTACTGAAGAGCATT 75 340 1158919 8217 8232 8416 8431 GATTAGTAGTCAAAGC  76 341 11589538331 8346 8530 8545 CATCAAGGATGTATAT 104 342 1158987 8448 8463 8647 8662CAGTAGGGCTTCTCAA  90 343

TABLE 35 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: NO: NO: 1 NO: 1 2824 2824 SEQ Compound Start StopStart Stop MALAT1 ID Number Site Site Site Site Sequence (5′ to 3′)(% UTC) No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC  77  18 559497 3629 3644 3829 3844 AGTACTATAGCATCTG 102  32  559564 2839 28543039 3054 CCATAAGTAAGTTCCA  45  36 1156453   16   31 N/A N/AAGTCTCGGGCTGCAGG  97 344 1156486  168  183  134  149 GACTCTGGGAAACCTG 99 345 1156519  264  279  230  245 CAGAGTTTGAGTGGTT  84 346 1156553 357  372  323  338 TGTGTTATGCCTGGTT  99 347 1156587  487  502  453  468AGTAGACCAACTAAGC  75 348 1156621  533  548  499  514 TCACAAGGCAAATCGC 93 349 1156655  613  628  579  594 CCCCAGTTGCCGCCAG 118 350 1156689 740  755  706  721 TGCTTGGGAAATCTTA  77 351 1156722  838  853  804  819GACTTTCTCCCCCAAC  94 352 1156756  896  911  862  877 TCCATTACGCAACTGA 91 353 1156790  961  976  927  942 GACAGTAGGTATAGTT 113 354 1156824 N/AN/A 1010 1025 TTTTAAACGGGTCATC  83 355 1156858 N/A N/A 1152 1167AGGTTCTAGTTTTACT  84 356 1156892 1019 1034 1219 1234 CACCGGAATTCGATCA 80 357 1156926 1073 1088 1273 1288 TGCCTACCGCACAGCT  81 358 11569601178 1193 1378 1393 AGTAGTTGTATTAATC  36 359 1156994 1336 1351 1536 1551TCTCAACCTCCGTCAT  73 360 1157027 1517 1532 1717 1732 TAAAAGATCGCCTTCA 59 361 1157060 1592 1607 1792 1807 AGGCTTTAAATGACGC 111 362 11570941865 1880 2065 2080 CTTCTAAGTTTGTACA  53 363 1157128 2134 2149 2334 2349AAATTGGTTCTGGTCT  52 364 1157162 2286 2301 2486 2501 CAAACTAAGCTACTAT 85 365 1157194 2346 2361 2546 2561 TAAGTTGGTAATTACT  83 366 11572282452 2467 2652 2667 AGATTCACTGAATCCA  94 367 1157262 2558 2573 2758 2773GGACTCTTTTCCTATC 104 368 1157296 2682 2697 2882 2897 CCTGCTACCTTCATCA 78 369 1157329 2759 2774 2959 2974 CACACTGGCATGCTGG  91 370 11573632818 2833 3018 3033 ACAACATATTGCCGAC  90 371 1157397 2897 2912 3097 3112TCCCTTTACACCTCAG  75 372 1157430 2975 2990 3175 3190 TCAGACAAGATTCATG 69 373 1157462 3136 3151 3336 3351 TTACCCCAACTAAACA 104 374 11574963238 3253 3438 3453 TCCCCCCCGCCTCAGT  84 375 1157529 3340 3355 3540 3555TACACCTTGAGTCATT  62 376 1157563 3451 3466 3651 3666 TCCAATGGACATCTCT 75 377 1157595 3633 3648 3833 3848 CAATAGTACTATAGCA  93 378 11576283723 3738 3923 3938 AATACTCTTCCAAGGA  85 379 1157662 3880 3895 4080 4095ATATTTGCCCCTCCCC  73 380 1157695 3947 3962 4147 4162 ACTAAACAATTACCTA 91 381 1157729 4092 4107 4292 4307 TAACTTCCCCCAGCTT  80 382 11577624192 4207 4392 4407 CCCCAAAAGCTCTATA  92 383 1157795 4285 4300 4485 4500CACTACCATATCCAAA  77 384 1157829 4449 4464 4649 4664 TTGCTTACACACAACT 82 385 1157862 4618 4633 4817 4832 CCACCCTCTAAGAGAC 117 386 11578944754 4769 4953 4968 ACTTATCAATTCACCA  72 387 1157928 4820 4835 5019 5034TAGTAAGAATCTCAGG  40 388 1157962 4922 4937 5121 5136 TTGACAAGCAATTAAC 93 389 1157996 5054 5069 5253 5268 TTCCAGGATTAATGTA  63 390 11580285141 5156 5340 5355 CTGAGGCAAACGAAAC 106 391 1158062 5227 5242 5426 5441GTTAAACTTATCTGTT  59 392 1158095 5295 5310 5494 5509 GATATTTAAGAACTCC 62 393 1158127 5392 5407 5591 5606 CACAGGAACAAGTCCT  84 394 11581605493 5508 5692 5707 CTTAGTTGGCATCAAG  69 395 1158194 5679 5694 5878 5893TAAGGAGACAGCTTTC  84 396 1158227 5779 5794 5978 5993 TTAAAGAGTGTTCGCA 41 397 1158260 5903 5918 6102 6117 TTAGAGGGCCTCTATT  97 398 11582935998 6013 6197 6212 TTTATAGACCCCTGAC  78 399 1158327 6087 6102 6286 6301ACATTGCCTACCACTC  84 400 1158361 6210 6225 6409 6424 GCACTCATATGCAATT 94 401 1158393 6329 6344 6528 6543 CAACAAGTAAGCCCCA 100 402 11584276440 6455 6639 6654 CTAATAGCAGCGGGAT  78 403 1158459 6541 6556 6740 6755CAGCCTTTATCACTCA  51 404 1158492 6700 6715 6899 6914 CTGATTTTAAGGTTGC 20 405 1158523 6973 6988 7172 7187 AAAGAACTAGTGGTTC 104 406 11585567087 7102 7286 7301 ACTGATCTGACTTTGT  68 407 1158589 7163 7178 7362 7377CCACGCCAACACAGTT  69 408 1158622 7314 7329 7513 7528 CTTCTCTTGACCTTAG 39 409 1158656 7421 7436 7620 7635 TTAAGAGAAGCCCAGG  76 410 11586897527 7542 7726 7741 TAGGGAAAAGTGGTTG 113 411 1158723 7658 7673 7857 7872AGGATCCAAGCTACTG 113 412 1158757 7712 7727 7911 7926 CCAAAGACCTCGACAC 87 413 1158789 7785 7800 7984 7999 GCTGTGGTTTTAATAC  51 414 11588237877 7892 8076 8091 CCCAGCATTACAGTTC  90 415 1158856 7988 8003 8187 8202TGTTATGTTCACCTGA  65 416 1158889 8044 8059 8243 8258 CCCTACTGAAGAGCAT 87 417 1158920 8218 8233 8417 8432 AGATTAGTAGTCAAAG 112 418 11589548332 8347 8531 8546 ACATCAAGGATGTATA 106 419 1158988 8449 8464 8648 8663GCAGTAGGGCTTCTCA 108 420

TABLE 36 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: NO: NO: 1 NO: 1 2824 2824 SEQ Compound Start StopStart Stop MALAT1 ID Number Site Site Site Site Sequence (5′ to 3′)(% UTC) No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC  78  18 559497 3629 3644 3829 3844 AGTACTATAGCATCTG  98  32  559564 2839 28543039 3054 CCATAAGTAAGTTCCA  39  36  946407 3452 3467 3652 3667CTCCAATGGACATCTC  71 421 1156454   17   32 N/A N/A AAGTCTCGGGCTGCAG  96422 1156487  201  216  167  182 AGATAGCAGCACAACT 105 423 1156520  265 280  231  246 GCAGAGTTTGAGTGGT 109 424 1156554  358  373  324  339CTGTGTTATGCCTGGT 103 425 1156588  488  503  454  469 AAGTAGACCAACTAAG122 426 1156622  534  549  500  515 CTCACAAGGCAAATCG 112 427 1156656 616  631  582  597 GCCCCCCAGTTGCCGC 135 428 1156690  751  766  717  732CACGGGCTGTCTGCTT  82 429 1156723  839  854  805  820 GGACTTTCTCCCCCAA105 430 1156757  897  912  863  878 TTCCATTACGCAACTG 121 431 1156791 962  977  928  943 GGACAGTAGGTATAGT  89 432 1156825 N/A N/A 1011 1026ATTTTAAACGGGTCAT  93 433 1156859 N/A N/A 1163 1178 CGGTTAAAAATAGGTT  94434 1156893 1020 1035 1220 1235 TCACCGGAATTCGATC 363 435 1156927 10741089 1274 1289 ATGCCTACCGCACAGC 108 436 1156961 1200 1215 1400 1415AACCTATTGACTATAT  81 437 1156995 1337 1352 1537 1552 ATCTCAACCTCCGTCA 66 438 1157028 1518 1533 1718 1733 TTAAAAGATCGCCTTC  57 439 11570611593 1608 1793 1808 TAGGCTTTAAATGACG  74 440 1157095 1866 1881 2066 2081TCTTCTAAGTTTGTAC  37 441 1157129 2135 2150 2335 2350 TAAATTGGTTCTGGTC 51 442 1157163 2287 2302 2487 2502 TCAAACTAAGCTACTA 101 443 11571952347 2362 2547 2562 TTAAGTTGGTAATTAC 106 444 1157229 2453 2468 2653 2668TAGATTCACTGAATCC 104 445 1157263 2571 2586 2771 2786 CGCACTGGCTCCTGGA 51 446 1157297 2683 2698 2883 2898 GCCTGCTACCTTCATC  64 447 11573302763 2778 2963 2978 TTGGCACACTGGCATG  76 448 1157364 2820 2835 3020 3035AAACAACATATTGCCG  80 449 1157398 2898 2913 3098 3113 ATCCCTTTACACCTCA 64 450 1157431 2976 2991 3176 3191 TTCAGACAAGATTCAT  49 451 11574633137 3152 3337 3352 ATTACCCCAACTAAAC  91 452 1157497 3239 3254 3439 3454CTCCCCCCCGCCTCAG  88 453 1157530 3341 3356 3541 3556 TTACACCTTGAGTCAT 79 454 1157596 3634 3649 3834 3849 TCAATAGTACTATAGC  75 455 11576293724 3739 3924 3939 GAATACTCTTCCAAGG  84 456 1157663 3881 3896 4081 4096AATATTTGCCCCTCCC  85 457 1157696 3959 3974 4159 4174 CTGCAATCATAAACTA 90 458 1157730 4093 4108 4293 4308 TTAACTTCCCCCAGCT 100 459 11577634210 4225 4410 4425 CAGTTCAATACTTTCC  55 460 1157796 4288 4303 4488 4503ACACACTACCATATCC 103 461 1157830 4453 4468 4653 4668 AAACTTGCTTACACAC 75 462 1157863 4619 4634 4818 4833 CCCACCCTCTAAGAGA 104 463 11578954755 4770 4954 4969 TACTTATCAATTCACC  46 464 1157929 

4821 4836 5020 5035 GTAGTAAGAATCTCAG  20   5 1157963 4923 4938 5122 5137CTTGACAAGCAATTAA  70 465 1157997 5056 5071 5255 5270 TATTCCAGGATTAATG 71 466 1158029 5143 5158 5342 5357 GTCTGAGGCAAACGAA  71 467 11580635230 5245 5429 5444 CAAGTTAAACTTATCT  84 468 1158096 5298 5313 5497 5512GTTGATATTTAAGAAC 115 469 1158128 5393 5408 5592 5607 CCACAGGAACAAGTCC105 470 1158161 

5494 5509 5693 5708 CCTTAGTTGGCATCAA  18   6 1158195 5683 5698 5882 5897TAAATAAGGAGACAGC  62 471 1158228 5780 5795 5979 5994 ATTAAAGAGTGTTCGC 31 472 1158261 5904 5919 6103 6118 TTTAGAGGGCCTCTAT  83 473 11582945999 6014 6198 6213 ATTTATAGACCCCTGA 108 474 1158328 6089 6104 6288 6303AAACATTGCCTACCAC 109 475 1158362 6212 6227 6411 6426 AAGCACTCATATGCAA102 476 1158394 6330 6345 6529 6544 ACAACAAGTAAGCCCC 107 477 11584286441 6456 6640 6655 TCTAATAGCAGCGGGA  84 478 1158460 6542 6557 6741 6756TCAGCCTTTATCACTC  87 479 1158493 6701 6716 6900 6915 ACTGATTTTAAGGTTG 74 480 1158524 6975 6990 7174 7189 TGAAAGAACTAGTGGT  77 481 11585577088 7103 7287 7302 AACTGATCTGACTTTG  66 482 1158590 7165 7180 7364 7379CCCCACGCCAACACAG  90 483 1158623 7317 7332 7516 7531 ACACTTCTCTTGACCT 40 484 1158657 7422 7437 7621 7636 GTTAAGAGAAGCCCAG  80 485 11586907528 7543 7727 7742 CTAGGGAAAAGTGGTT 122 486 1158724 7659 7674 7858 7873AAGGATCCAAGCTACT  92 487 1158758 7713 7728 7912 7927 ACCAAAGACCTCGACA 86 488 1158790 7791 7806 7990 8005 TACTTAGCTGTGGTTT  77 489 11588247878 7893 8077 8092 ACCCAGCATTACAGTT  92 490 1158857 7989 8004 8188 8203CTGTTATGTTCACCTG  44 491 1158890 8046 8061 8245 8260 GACCCTACTGAAGAGC 68 492 1158921 8220 8235 8419 8434 ACAGATTAGTAGTCAA  91 493 11589558333 8348 8532 8547 TACATCAAGGATGTAT  98 494 1158989 8450 8465 8649 8664AGCAGTAGGGCTTCTC  97 495

TABLE 37 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: NO: NO: 1 NO: 1 2824 2824 SEQ Compound Start StopStart Stop MALAT1 ID Number Site Site Site Site Sequence (5′ to 3′)(% UTC) No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC  93  18 559497 3629 3644 3829 3844 AGTACTATAGCATCTG 107  32  559564 2839 28543039 3054 CCATAAGTAAGTTCCA  34  36  946421 7423 7438 7622 7637TGTTAAGAGAAGCCCA  98 496  946426 8451 8466 8650 8665 CAGCAGTAGGGCTTCT101 497 1156455   18   33 N/A N/A GAAGTCTCGGGCTGCA  94 498 1156488  202 217  168  183 AAGATAGCAGCACAAC  88 499 1156521  267  282  233  248CTGCAGAGTTTGAGTG 119 500 1156555  359  374  325  340 TCTGTGTTATGCCTGG 83 501 1156589  490  505  456  471 TAAAGTAGACCAACTA  86 502 1156623 535  550  501  516 GCTCACAAGGCAAATC 104 503 1156657  618  633  584  599CGGCCCCCCAGTTGCC  83 504 1156691  752  767  718  733 GCACGGGCTGTCTGCT112 505 1156724  840  855  806  821 CGGACTTTCTCCCCCA 109 506 1156758 899  914  865  880 CTTTCCATTACGCAAC 100 507 1156792  964  979  930  945AGGGACAGTAGGTATA  84 508 1156826 N/A N/A 1012 1027 TATTTTAAACGGGTCA  97509 1156860 N/A N/A 1164 1179 TCGGTTAAAAATAGGT  84 510 1156894 1021 10361221 1236 ATCACCGGAATTCGAT  83 511 1156928 1076 1091 1276 1291CAATGCCTACCGCACA  84 512 1156962 1201 1216 1401 1416 TAACCTATTGACTATA 78 513 1156996 1339 1354 1539 1554 TCATCTCAACCTCCGT  43 514 11570291519 1534 1719 1734 TTTAAAAGATCGCCTT  50 515 1157062 1597 1612 1797 1812TAACTAGGCTTTAAAT  86 516 1157096 1923 1938 2123 2138 CTATCTGAAACTCTTG 43 517 1157130 2136 2151 2336 2351 CTAAATTGGTTCTGGT  34 518 11571642288 2303 2488 2503 TTCAAACTAAGCTACT  69 519 1157196 2349 2364 2549 2564CATTAAGTTGGTAATT  88 520 1157230 2454 2469 2654 2669 CTAGATTCACTGAATC 93 521 1157264 2572 2587 2772 2787 TCGCACTGGCTCCTGG  58 522 11572982684 2699 2884 2899 CGCCTGCTACCTTCAT  70 523 1157331 2769 2784 2969 2984GTGGCCTTGGCACACT 110 524 1157365 2838 2853 3038 3053 CATAAGTAAGTTCCAG 51 525 1157399 2899 2914 3099 3114 AATCCCTTTACACCTC  74 526 11574322977 2992 3177 3192 CTTCAGACAAGATTCA  76 527 1157464 3138 3153 3338 3353CATTACCCCAACTAAA  85 528 1157498 3240 3255 3440 3455 ACTCCCCCCCGCCTCA 74 529 1157531 3342 3357 3542 3557 GTTACACCTTGAGTCA  47 530 11575643453 3468 3653 3668 TCTCCAATGGACATCT  92 531 1157597 3635 3650 3835 3850GTCAATAGTACTATAG  42 532 1157630 3725 3740 3925 3940 GGAATACTCTTCCAAG 94 533 1157664 3882 3897 4082 4097 CAATATTTGCCCCTCC  70 534 11576973965 3980 4165 4180 GTTTATCTGCAATCAT  43 535 1157731 4094 4109 4294 4309TTTAACTTCCCCCAGC 102 536 1157764 4211 4226 4411 4426 CCAGTTCAATACTTTC 87 537 1157797 4290 4305 4490 4505 CCACACACTACCATAT  83 538 11578314496 4511 4695 4710 TGCAGTTAAACAATGG  38 539 1157864 4620 4635 4819 4834GCCCACCCTCTAAGAG  82 540 1157896 4761 4776 4960 4975 TGCCTTTACTTATCAA 74 541 1157930 4823 4838 5022 5037 CAGTAGTAAGAATCTC  46 542 11579644924 4939 5123 5138 GCTTGACAAGCAATTA  65 543 1157998 5057 5072 5256 5271TTATTCCAGGATTAAT 105 544 1158030 5145 5160 5344 5359 CTGTCTGAGGCAAACG 63 545 1158064 5231 5246 5430 5445 GCAAGTTAAACTTATC  58 546 11580975304 5319 5503 5518 GCCATGGTTGATATTT  91 547 1158129 5394 5409 5593 5608CCCACAGGAACAAGTC  86 548 1158162 

5495 5510 5694 5709 TCCTTAGTTGGCATCA  24   7 1158196 5706 5721 5905 5920CTACAGACAAACACTA  94 549 1158229 5781 5796 5980 5995 CATTAAAGAGTGTTCG 66 550 1158262 5906 5921 6105 6120 TATTTAGAGGGCCTCT  66 551 11582956000 6015 6199 6214 AATTTATAGACCCCTG  96 552 1158329 6092 6107 6291 6306GTAAAACATTGCCTAC  76 553 1158363 6214 6229 6413 6428 CCAAGCACTCATATGC 88 554 1158395 6331 6346 6530 6545 TACAACAAGTAAGCCC  80 555 11584296442 6457 6641 6656 TTCTAATAGCAGCGGG  41 556 1158461 6544 6559 6743 6758ACTCAGCCTTTATCAC 105 557 1158494 6715 6730 6914 6929 GAATGTTTCTTGTCAC 57 558 1158525 6976 6991 7175 7190 CTGAAAGAACTAGTGG  80 559 11585587089 7104 7288 7303 TAACTGATCTGACTTT  74 560 1158591 7167 7182 7366 7381ACCCCCACGCCAACAC  77 561 1158624 7319 7334 7518 7533 TGACACTTCTCTTGAC 70 562 1158691 7529 7544 7728 7743 GCTAGGGAAAAGTGGT  95 563 11587257660 7675 7859 7874 CAAGGATCCAAGCTAC  81 564 1158759 7714 7729 7913 7928CACCAAAGACCTCGAC  82 565 1158791 7792 7807 7991 8006 CTACTTAGCTGTGGTT 67 566 1158825 7881 7896 8080 8095 CCCACCCAGCATTACA  82 567 11588587990 8005 8189 8204 TCTGTTATGTTCACCT  48 568 1158891 8047 8062 8246 8261TGACCCTACTGAAGAG  79 569 1158922 8221 8236 8420 8435 GACAGATTAGTAGTCA112 570 1158956 8334 8349 8533 8548 ATACATCAAGGATGTA  81 571

TABLE 38 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: NO: NO: 1 NO: 1 2824 2824 SEQ Compound Start StopStart Stop MALAT1 ID Number Site Site Site Site Sequence (5′ to 3′)(% UTC) No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC 110  18 559497 3629 3644 3829 3844 AGTACTATAGCATCTG 115  32  559564 2839 28543039 3054 CCATAAGTAAGTTCCA  60  36 1156456   19   34 N/A N/AAGAAGTCTCGGGCTGC  92 572 1156489  203  218  169  184 TAAGATAGCAGCACAA103 573 1156522  274  289  240  255 GACCAAACTGCAGAGT  97 574 1156556 365  380  331  346 GCAGATTCTGTGTTAT 102 575 1156590  491  506  457  472TTAAAGTAGACCAACT  73 576 1156624  539  554  505  520 AAGTGCTCACAAGGCA116 577 1156658  619  634  585  600 GCGGCCCCCCAGTTGC 116 578 1156692 753  768  719  734 AGCACGGGCTGTCTGC  93 579 1156725  841  856  807  822GCGGACTTTCTCCCCC 124 580 1156759  900  915  866  881 ACTTTCCATTACGCAA 91 581 1156793  965  980  931  946 GAGGGACAGTAGGTAT  81 582 1156827 N/AN/A 1013 1028 ATATTTTAAACGGGTC  84 583 1156861 N/A N/A 1165 1180TTCGGTTAAAAATAGG 107 584 1156895 1022 1037 1222 1237 CATCACCGGAATTCGA 98 585 1156929 1077 1092 1277 1292 TCAATGCCTACCGCAC  97 586 11569631202 1217 1402 1417 GTAACCTATTGACTAT  67 587 1156997 1348 1363 1548 1563GAAGAAGCTTCATCTC  85 588 1157030 1520 1535 1720 1735 TTTTAAAAGATCGCCT 67 589 1157063 1599 1614 1799 1814 GTTAACTAGGCTTTAA  77 590 11570971948 1963 2148 2163 CTTGTCTTAGCTTGTT  29 591 1157131 2137 2152 2337 2352TCTAAATTGGTTCTGG  45 592 1157165 2305 2320 2505 2520 GAAAGTCCTTCACATT 78 593 1157197 2350 2365 2550 2565 ACATTAAGTTGGTAAT  96 594 11572312463 2478 2663 2678 GCTGTCTTCCTAGATT  64 595 1157265 2574 2589 2774 2789AATCGCACTGGCTCCT  75 596 1157299 2686 2701 2886 2901 GCCGCCTGCTACCTTC 88 597 1157332 2778 2793 2978 2993 GCTTTCCCTGTGGCCT  90 598 11573662840 2855 3040 3055 ACCATAAGTAAGTTCC  42 599 1157400 2900 2915 3100 3115AAATCCCTTTACACCT  77 600 1157433 3001 3016 3201 3216 GACTTGGCAGTCTGCC 90 601 1157465 3139 3154 3339 3354 TCATTACCCCAACTAA  83 602 11574993241 3256 3441 3456 AACTCCCCCCCGCCTC  94 603 1157532 3343 3358 3543 3558TGTTACACCTTGAGTC  63 604 1157565 3457 3472 3657 3672 CATTTCTCCAATGGAC 88 605 1157598 3636 3651 3836 3851 TGTCAATAGTACTATA  82 606 11576313726 3741 3926 3941 GGGAATACTCTTCCAA  86 607 1157665 3883 3898 4083 4098CCAATATTTGCCCCTC  60 608 1157698 3966 3981 4166 4181 AGTTTATCTGCAATCA 54 609 1157732 4095 4110 4295 4310 ATTTAACTTCCCCCAG  82 610 11577654212 4227 4412 4427 CCCAGTTCAATACTTT  75 611 1157798 4292 4307 4492 4507AACCACACACTACCAT 107 612 1157832 4513 4528 4712 4727 ACCTTAACATCTTGTT 85 613 1157865 4622 4637 4821 4836 AAGCCCACCCTCTAAG  79 614 11578974762 4777 4961 4976 CTGCCTTTACTTATCA  56 615 1157931 4824 4839 5023 5038TCAGTAGTAAGAATCT  44 616 1157965 4925 4940 5124 5139 AGCTTGACAAGCAATT 84 617 1157999 5068 5083 5267 5282 TTCGGCTTCTTTTATT  56 618 11580315150 5165 5349 5364 GATACCTGTCTGAGGC  67 619 1158065 5232 5247 5431 5446TGCAAGTTAAACTTAT  75 620 1158098 5305 5320 5504 5519 TGCCATGGTTGATATT 63 621 1158130 5395 5410 5594 5609 GCCCACAGGAACAAGT  75 622 11581635496 5511 5695 5710 TTCCTTAGTTGGCATC  26 623 1158197 5718 5733 5917 5932CCCAACACTGAACTAC  81 624 1158230 5782 5797 5981 5996 CCATTAAAGAGTGTTC 36 625 1158263 5907 5922 6106 6121 TTATTTAGAGGGCCTC  43 626 11582966001 6016 6200 6215 CAATTTATAGACCCCT 106 627 1158330 6093 6108 6292 6307TGTAAAACATTGCCTA 107 628 1158364 6215 6230 6414 6429 GCCAAGCACTCATATG 76 629 1158396 6332 6347 6531 6546 CTACAACAAGTAAGCC  93 630 11584306443 6458 6642 6657 ATTCTAATAGCAGCGG  68 631 1158462 6548 6563 6747 6762CAACACTCAGCCTTTA 101 632 1158495 6730 6745 6929 6944 ACTGTTGCTTGTTTGG 47 633 1158526 6985 7000 7184 7199 GAATACCATCTGAAAG  84 634 11585597090 7105 7289 7304 ATAACTGATCTGACTT 105 635 1158592 7170 7185 7369 7384TCCACCCCCACGCCAA 109 636 1158625 7321 7336 7520 7535 GCTGACACTTCTCTTG 52 637 1158658 7424 7439 7623 7638 ATGTTAAGAGAAGCCC 117 638 11586927530 7545 7729 7744 AGCTAGGGAAAAGTGG 110 639 1158726 7661 7676 7860 7875ACAAGGATCCAAGCTA 107 640 1158760 7715 7730 7914 7929 CCACCAAAGACCTCGA 73 641 1158792 7793 7808 7992 8007 GCTACTTAGCTGTGGT  72 642 11588267882 7897 8081 8096 TCCCACCCAGCATTAC  73 643 1158859 7992 8007 8191 8206AGTCTGTTATGTTCAC  46 644 1158892 8048 8063 8247 8262 ATGACCCTACTGAAGA 85 645 1158923 8222 8237 8421 8436 AGACAGATTAGTAGTC 108 646 11589578336 8351 8535 8550 TTATACATCAAGGATG  96 647 1158990 8457 8472 8656 8671AGTTTTCAGCAGTAGG 121 648

TABLE 39 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: NO: NO: 1 NO: 1 2824 2824 SEQ Compound Start StopStart Stop MALAT1 ID Number Site Site Site Site Sequence (5′ to 3′)(% UTC) No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC  82  18 556110 7198 7213 7397 7412 AAAAAAGGCTTAGCGC 100 649  559497 3629 36443829 3844 AGTACTATAGCATCTG 131  32  559564 2839 2854 3039 3054CCATAAGTAAGTTCCA  39  36 1156457   20   35 N/A N/A CAGAAGTCTCGGGCTG  81650 1156490  204  219  170  185 CTAAGATAGCAGCACA  89 651 1156523  277 292  243  258 CAAGACCAAACTGCAG 128 652 1156557  406  421  372  387TTACACTGCTCTGGGT  98 653 1156591  492  507  458  473 TTTAAAGTAGACCAAC149 654 1156625  541  556  507  522 GAAAGTGCTCACAAGG  94 655 1156659 620  635  586  601 TGCGGCCCCCCAGTTG 106 656 1156693  754  769  720  735CAGCACGGGCTGTCTG 133 657 1156726  842  857  808  823 GGCGGACTTTCTCCCC117 658 1156760  901  916  867  882 TACTTTCCATTACGCA  84 659 1156794 966  981  932  947 TGAGGGACAGTAGGTA  82 660 1156828 N/A N/A 1014 1029CATATTTTAAACGGGT 116 661 1156862 N/A N/A 1166 1181 CTTCGGTTAAAAATAG  96662 1156896 1025 1040 1225 1240 TCGCATCACCGGAATT  96 663 1156930 10791094 1279 1294 CCTCAATGCCTACCGC  83 664 1156964 1203 1218 1403 1418AGTAACCTATTGACTA 116 665 1156998 1354 1369 1554 1569 CTCCATGAAGAAGCTT 51 666 1157031 1522 1537 1722 1737 CTTTTTAAAAGATCGC  69 667 11570641600 1615 1800 1815 CGTTAACTAGGCTTTA  48 668 1157098 1950 1965 2150 2165TACTTGTCTTAGCTTG  49 669 1157132 2140 2155 2340 2355 TCTTCTAAATTGGTTC 51 670 1157166 2307 2322 2507 2522 ACGAAAGTCCTTCACA  89 671 11571982363 2378 2563 2578 GTCCAATGCAAAAACA 105 672 1157232 2477 2492 2677 2692GAATCCTGTCTGCTGC  67 673 1157266 2575 2590 2775 2790 AAATCGCACTGGCTCC 94 674 1157300 2688 2703 2888 2903 AAGCCGCCTGCTACCT 116 675 11573332779 2794 2979 2994 CGCTTTCCCTGTGGCC 102 676 1157367 2841 2856 3041 3056TACCATAAGTAAGTTC  96 677 1157401 2901 2916 3101 3116 TAAATCCCTTTACACC 88 678 1157434 3002 3017 3202 3217 GGACTTGGCAGTCTGC  73 679 11574663140 3155 3340 3355 TTCATTACCCCAACTA  58 680 1157500 3243 3258 3443 3458AAAACTCCCCCCCGCC 104 681 1157533 3344 3359 3544 3559 CTGTTACACCTTGAGT 67 682 1157566 3466 3481 3666 3681 ACTACCAGCCATTTCT  51 683 11575993640 3655 3840 3855 AGTTTGTCAATAGTAC  58 684 1157632 3727 3742 3927 3942TGGGAATACTCTTCCA  89 685 1157666 3885 3900 4085 4100 TGCCAATATTTGCCCC 80 686 1157699 3970 3985 4170 4185 CATGAGTTTATCTGCA 106 687 11577334097 4112 4297 4312 ATATTTAACTTCCCCC  70 688 1157766 4213 4228 4413 4428CCCCAGTTCAATACTT  75 689 1157799 4294 4309 4494 4509 AGAACCACACACTACC 77 690 1157833 4514 4529 4713 4728 TACCTTAACATCTTGT  86 691 11578664623 4638 4822 4837 AAAGCCCACCCTCTAA 126 692 1157898 4781 4796 4980 4995GTATGACATATAATCT  45 693 1157932 4825 4840 5024 5039 ATCAGTAGTAAGAATC 77 694 1157966 4926 4941 5125 5140 TAGCTTGACAAGCAAT  88 695 11580005070 5085 5269 5284 ATTTCGGCTTCTTTTA  43 696 1158032 5151 5166 5350 5365AGATACCTGTCTGAGG  88 697 1158066 5236 5251 5435 5450 CAGATGCAAGTTAAAC 60 698 1158099 5310 5325 5509 5524 GAAAGTGCCATGGTTG  59 699 11581315408 5423 5607 5622 TCCCATCACTGAAGCC  56 700 1158164 5498 5513 5697 5712ATTTCCTTAGTTGGCA  28 701 1158198 5720 5735 5919 5934 GCCCCAACACTGAACT 89 702 1158231 5783 5798 5982 5997 TCCATTAAAGAGTGTT  44 703 11582645908 5923 6107 6122 CTTATTTAGAGGGCCT  64 704 1158297 6002 6017 6201 6216TCAATTTATAGACCCC  53 705 1158331 6094 6109 6293 6308 GTGTAAAACATTGCCT100 706 1158365 6216 6231 6415 6430 AGCCAAGCACTCATAT  83 707 11583976333 6348 6532 6547 GCTACAACAAGTAAGC  91 708 1158431 6444 6459 6643 6658CATTCTAATAGCAGCG  49 709 1158463 6575 6590 6774 6789 GACTGCTTAAAACTGC 64 710 1158496 6732 6747 6931 6946 AGACTGTTGCTTGTTT  99 711 11585276988 7003 7187 7202 GAAGAATACCATCTGA  95 712 1158560 7091 7106 7290 7305CATAACTGATCTGACT 105 713 1158626 7322 7337 7521 7536 GGCTGACACTTCTCTT 48 714 1158659 7455 7470 7654 7669 TTAAGAGCTGCTATAA  94 715 11586937537 7552 7736 7751 CTGGAAAAGCTAGGGA 113 716 1158727 7662 7677 7861 7876CACAAGGATCCAAGCT  82 717 1158761 7716 7731 7915 7930 CCCACCAAAGACCTCG 69 718 1158793 7794 7809 7993 8008 AGCTACTTAGCTGTGG  66 719 11588277889 7904 8088 8103 TACATGTTCCCACCCA  61 720 1158860 7997 8012 8196 8211GGCCAAGTCTGTTATG 101 721 1158893 8049 8064 8248 8263 CATGACCCTACTGAAG 98 722 1158924 8227 8242 8426 8441 CCTGAAGACAGATTAG  76 723 11589588337 8352 8536 8551 ATTATACATCAAGGAT  83 724 1158991 8458 8473 8657 8672AAGTTTTCAGCAGTAG  92 725

TABLE 40 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ SEQ NO: NO: ID NO: ID NO: 2824 2824 Compound 1 Start 1 Stop StartStop MALAT1 SEQ Number Site Site Site Site Sequence (5′ to 3′) (% UTC)ID No. 395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC 81 18 559497 36293644 3829 3844 AGTACTATAGCATCTG 132 32 559564 2839 2854 3039 3054CCATAAGTAAGTTCCA 49 36 946416 5909 5924 6108 6123 CCTTATTTAGAGGGCC 67726 1156458 21 36 N/A N/A ACAGAAGTCTCGGGCT 81 727 1156491 205 220 171186 GCTAAGATAGCAGCAC 71 728 1156524 280 295 246 261 CCCCAAGACCAAACTG 109729 1156558 410 425 376 391 GTGTTTACACTGCTCT 94 730 1156592 495 510 461476 CCTTTTAAAGTAGACC 122 731 1156626 545 560 511 526 TCCTGAAAGTGCTCAC107 732 1156660 621 636 587 602 CTGCGGCCCCCCAGTT 75 733 1156694 756 771722 737 AGCAGCACGGGCTGTC 90 734 1156727 843 858 809 824 TGGCGGACTTTCTCCC91 735 1156761 902 917 868 883 TTACTTTCCATTACGC 84 736 1156795 967 982933 948 TTGAGGGACAGTAGGT 79 737 1156829 N/A N/A 1015 1030TCATATTTTAAACGGG 77 738 1156863 N/A N/A 1167 1182 TCTTCGGTTAAAAATA 81739 1156897 1026 1041 1226 1241 CTCGCATCACCGGAAT 114 740 1156931 10801095 1280 1295 GCCTCAATGCCTACCG 111 741 1156965 1204 1219 1404 1419TAGTAACCTATTGACT 136 742 1156999 1356 1371 1556 1571 TACTCCATGAAGAAGC126 743 1157032 1533 1548 1733 1748 CGGTTTAATCTCTTTT 20 744 1157065 16401655 1840 1855 CCCAATTAATCTTTCC 53 745 1157099 1951 1966 2151 2166ATACTTGTCTTAGCTT 40 746 1157133 2156 2171 2356 2371 TTCTAGCTTCAAGTAT 75747 1157167 2308 2323 2508 2523 TACGAAAGTCCTTCAC 65 748 1157199 23642379 2564 2579 AGTCCAATGCAAAAAC 77 749 1157233 2479 2494 2679 2694TGGAATCCTGTCTGCT 83 750 1157267 2577 2592 2777 2792 CCAAATCGCACTGGCT 84751 1157301 2691 2706 2891 2906 GCCAAGCCGCCTGCTA 80 752 1157334 27812796 2981 2996 CTCGCTTTCCCTGTGG 83 753 1157368 2842 2857 3042 3057TTACCATAAGTAAGTT 120 754 1157402 2908 2923 3108 3123 CCCCATATAAATCCCT107 755 1157435 3003 3018 3203 3218 AGGACTTGGCAGTCTG 70 756 1157467 31413156 3341 3356 CTTCATTACCCCAACT 86 757 1157501 3244 3259 3444 3459GAAAACTCCCCCCCGC 104 758 1157534 3345 3360 3545 3560 TCTGTTACACCTTGAG 52759 1157567 3468 3483 3668 3683 TAACTACCAGCCATTT 76 760 1157600 36413656 3841 3856 CAGTTTGTCAATAGTA 48 761 1157633 3729 3744 3929 3944ACTGGGAATACTCTTC 72 762 1157667 3894 3909 4094 4109 CCAACTAATTGCCAAT 60763 1157700 3974 3989 4174 4189 CTGGCATGAGTTTATC 73 764 1157734 40984113 4298 4313 CATATTTAACTTCCCC 75 765 1157767 4216 4231 4416 4431AACCCCCAGTTCAATA 80 766 1157800 4296 4311 4496 4511 AGAGAACCACACACTA 72767 1157834 4515 4530 4714 4729 ATACCTTAACATCTTG 57 768 1157867 46304645 4829 4844 ATCAACAAAAGCCCAC 112 769 1157899 4783 4798 4982 4997AGGTATGACATATAAT 65 770 1157933 4826 4841 5025 5040 CATCAGTAGTAAGAAT 86771 1157967 4928 4943 5127 5142 TATAGCTTGACAAGCA 81 772 1158001 50715086 5270 5285 TATTTCGGCTTCTTTT 53 773 1158033 5152 5167 5351 5366GAGATACCTGTCTGAG 60 774 1158067 5238 5253 5437 5452 TGCAGATGCAAGTTAA 51775 1158100 5312 5327 5511 5526 GAGAAAGTGCCATGGT 74 776 1158132 54095424 5608 5623 ATCCCATCACTGAAGC 64 777 1158165 5499 5514 5698 5713AATTTCCTTAGTTGGC 32 778 1158199 5722 5737 5921 5936 TTGCCCCAACACTGAA 93779 1158232 5784 5799 5983 5998 GTCCATTAAAGAGTGT 53 780 1158298 60036018 6202 6217 GTCAATTTATAGACCC 82 781 1158332 6095 6110 6294 6309AGTGTAAAACATTGCC 93 782 1158366 6217 6232 6416 6431 GAGCCAAGCACTCATA 94783 1158398 6334 6349 6533 6548 AGCTACAACAAGTAAG 88 784 1158432 64476462 6646 6661 ATGCATTCTAATAGCA 101 785 1158464 6578 6593 6777 6792TACGACTGCTTAAAAC 95 786 1158497 6734 6749 6933 6948 GAAGACTGTTGCTTGT 48787 1158528 6989 7004 7188 7203 TGAAGAATACCATCTG 70 788 1158561 70927107 7291 7306 CCATAACTGATCTGAC 87 789 1158593 7215 7230 7414 7429GTACCTGAAAAATCTT 97 790 1158627 7324 7339 7523 7538 GAGGCTGACACTTCTC 110791 1158660 7456 7471 7655 7670 ATTAAGAGCTGCTATA 104 792 1158694 75387553 7737 7752 TCTGGAAAAGCTAGGG 121 793 1158728 7663 7678 7862 7877CCACAAGGATCCAAGC 120 794 1158762 7717 7732 7916 7931 ACCCACCAAAGACCTC 91795 1158794 7796 7811 7995 8010 AGAGCTACTTAGCTGT 84 796 1158828 78907905 8089 8104 TTACATGTTCCCACCC 81 797 1158861 8002 8017 8201 8216AGCTTGGCCAAGTCTG 72 798 1158894 8052 8067 8251 8266 CTTCATGACCCTACTG 64799 1158925 8239 8254 8438 8453 TACAGAAAGAGTCCTG 83 800 1158959 83468361 8545 8560 TCCTGACAAATTATAC 72 801 1158992 8459 8474 8658 8673TAAGTTTTCAGCAGTA 114 802

TABLE 41 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: NO: NO: 1 NO: 1 2824 2824 SEQ Compound Start StopStart Stop MALAT1 ID Number Site Site Site Site Sequence (5′ to 3′)(% UTC) No. 395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC 101 18559497 3629 3644 3829 3844 AGTACTATAGCATCTG 121 32 559564 2839 2854 30393054 CCATAAGTAAGTTCCA 36 36 568504 7891 7906 8090 8105 GTTACATGTTCCCACC63 803 946400 757 772 723 738 GAGCAGCACGGGCTGT 86 804 946405 2692 27072892 2907 AGCCAAGCCGCCTGCT 80 805 1156459 22 37 N/A N/A TACAGAAGTCTCGGGC72 806 1156492 207 222 173 188 CAGCTAAGATAGCAGC 92 807 1156525 282 297248 263 AACCCCAAGACCAAAC 89 808 1156559 411 426 377 392 AGTGTTTACACTGCTC78 809 1156593 497 512 463 478 GGCCTTTTAAAGTAGA 72 810 1156627 566 581532 547 CGTTTTTCAGCTTCCA 93 811 1156661 622 637 588 603 TCTGCGGCCCCCCAGT75 812 1156728 844 859 810 825 ATGGCGGACTTTCTCC 71 813 1156762 903 918869 884 TTTACTTTCCATTACG 84 814 1156796 969 984 935 950 TCTTGAGGGACAGTAG107 815 1156830 N/A N/A 1016 1031 ATCATATTTTAAACGG 68 816 1156864 N/AN/A 1168 1183 TTCTTCGGTTAAAAAT 98 817 1156898 1027 1042 1227 1242ACTCGCATCACCGGAA 85 818 1156932 1082 1097 1282 1297 CTGCCTCAATGCCTAC 56819 1156966 1205 1220 1405 1420 TTAGTAACCTATTGAC 66 820 1157000 13991414 1599 1614 GCTCTGTAGTCCTTTC 58 821 1157033 1534 1549 1734 1749TCGGTTTAATCTCTTT 37 822 1157066 1642 1657 1842 1857 CTCCCAATTAATCTTT 73823 1157100 1952 1967 2152 2167 AATACTTGTCTTAGCT 59 824 1157134 21592174 2359 2374 CCCTTCTAGCTTCAAG 62 825 1157168 2309 2324 2509 2524TTACGAAAGTCCTTCA 72 826 1157200 2369 2384 2569 2584 CTCAAAGTCCAATGCA 52827 1157234 2490 2505 2690 2705 ACACTGGTTCCTGGAA 52 828 1157268 25782593 2778 2793 ACCAAATCGCACTGGC 97 829 1157335 2782 2797 2982 2997ACTCGCTTTCCCTGTG 65 830 1157369 2843 2858 3043 3058 GTTACCATAAGTAAGT 98831 1157403 2911 2926 3111 3126 CGTCCCCATATAAATC 99 832 1157436 30043019 3204 3219 CAGGACTTGGCAGTCT 86 833 1157468 3143 3158 3343 3358TACTTCATTACCCCAA 66 834 1157502 3245 3260 3445 3460 TGAAAACTCCCCCCCG 79835 1157535 3346 3361 3546 3561 TTCTGTTACACCTTGA 41 836 1157568 34693484 3669 3684 GTAACTACCAGCCATT 55 837 1157601 3643 3658 3843 3858CCCAGTTTGTCAATAG 61 838 1157634 3730 3745 3930 3945 AACTGGGAATACTCTT 78839 1157668 3895 3910 4095 4110 GCCAACTAATTGCCAA 67 840 1157701 39854000 4185 4200 CTTTAAGTTCTCTGGC 36 841 1157735 4102 4117 4302 4317GGCTCATATTTAACTT 80 842 1157768 4218 4233 4418 4433 CCAACCCCCAGTTCAA 76843 1157801 4302 4317 4502 4517 TCCAAAAGAGAACCAC 79 844 1157835 45164531 4715 4730 CATACCTTAACATCTT 68 845 1157868 4632 4647 4831 4846TCATCAACAAAAGCCC 108 846 1157900 4784 4799 4983 4998 GAGGTATGACATATAA 46847 1157934 4829 4844 5028 5043 TCTCATCAGTAGTAAG 45 848 1157968 49294944 5128 5143 TTATAGCTTGACAAGC 63 849 1158002 5074 5089 5273 5288ATTTATTTCGGCTTCT 29 850 1158034 5153 5168 5352 5367 AGAGATACCTGTCTGA 78851 1158068 5239 5254 5438 5453 CTGCAGATGCAAGTTA 51 852 1158101 53185333 5517 5532 GGTCAGGAGAAAGTGC 82 853 1158133 5413 5428 5612 5627TACTATCCCATCACTG 58 854 1158166 5500 5515 5699 5714 AAATTTCCTTAGTTGG 46855 1158200 5725 5740 5924 5939 AGATTGCCCCAACACT 62 856 1158233 57905805 5989 6004 GATCTGGTCCATTAAA 75 857 1158265 5910 5925 6109 6124TCCTTATTTAGAGGGC 71 858 1158299 6004 6019 6203 6218 TGTCAATTTATAGACC 94859 1158333 6096 6111 6295 6310 TAGTGTAAAACATTGC 65 860 1158367 62196234 6418 6433 AAGAGCCAAGCACTCA 88 861 1158399 6335 6350 6534 6549AAGCTACAACAAGTAA 90 862 1158433 6448 6463 6647 6662 AATGCATTCTAATAGC 83863 1158465 6579 6594 6778 6793 ATACGACTGCTTAAAA 80 864 1158498 67376752 6936 6951 CTTGAAGACTGTTGCT 58 865 1158529 6991 7006 7190 7205TCTGAAGAATACCATC 85 866 1158562 7093 7108 7292 7307 CCCATAACTGATCTGA 58867 1158594 7234 7249 7433 7448 TCGGTGCCTTTAGTGA 71 868 1158628 73277342 7526 7541 GGTGAGGCTGACACTT 73 869 1158661 7457 7472 7656 7671TATTAAGAGCTGCTAT 75 870 1158695 7540 7555 7739 7754 CTTCTGGAAAAGCTAG 92871 1158729 7664 7679 7863 7878 CCCACAAGGATCCAAG 91 872 1158763 77197734 7918 7933 CAACCCACCAAAGACC 98 873 1158795 7797 7812 7996 8011TAGAGCTACTTAGCTG 82 874 1158862 8003 8018 8202 8217 TAGCTTGGCCAAGTCT 81875 1158895 8055 8070 8254 8269 AACCTTCATGACCCTA 80 876 1158926 82668281 8465 8480 ACTAGCACCTGCAGAG 77 877 1158960 8347 8362 8546 8561CTCCTGACAAATTATA 83 878 1158993 8461 8476 8660 8675 GTTAAGTTTTCAGCAG 83879

TABLE 42 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ NO: NO: NO: 1 ID NO: 2824 2824 Compound Start 1 Stop StartStop MALAT1 SEQ Number Site Site Site Site Sequence (5′ to 3′) (% UTC)ID No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC 103 18  5594973629 3644 3829 3844 AGTACTATAGCATCTG 137 32  559564 2839 2854 3039 3054CCATAAGTAAGTTCCA 53 36  568486 6220 6235 6419 6434 GAAGAGCCAAGCACTC 109880 1156460 23 38 N/A N/A TTACAGAAGTCTCGGG 89 881 1156493 208 223 174189 ACAGCTAAGATAGCAG 98 882 1156526 316 331 282 297 CCGGAGCAGGAAGAAA 77883 1156560 413 428 379 394 GAAGTGTTTACACTGC 89 884 1156594 499 514 465480 GTGGCCTTTTAAAGTA 85 885 1156628 567 582 533 548 CCGTTTTTCAGCTTCC 94886 1156662 623 638 589 604 ATCTGCGGCCCCCCAG 108 887 1156695 762 777 728743 AATCGGAGCAGCACGG 74 888 1156729 845 860 811 826 AATGGCGGACTTTCTC 100889 1156763 907 922 873 888 GGGCTTTACTTTCCAT 84 890 1156797 970 985 936951 CTCTTGAGGGACAGTA 96 891 1156831 N/A N/A 1046 1061 CTGCAAACTTTAGACA93 892 1156865 N/A N/A 1171 1186 TAGTTCTTCGGTTAAA 94 893 1156899 10281043 1228 1243 AACTCGCATCACCGGA 79 894 1156933 1090 1105 1290 1305TGCGCTGGCTGCCTCA 75 895 1156967 1206 1221 1406 1421 CTTAGTAACCTATTGA 66896 1157001 1416 1431 1616 1631 ATTGGTATTAATTCGG 30 897 1157034※ 15351550 1735 1750 TTCGGTTTAATCTCTT 25 2 1157067 1644 1659 1844 1859CACTCCCAATTAATCT 92 898 1157101 1954 1969 2154 2169 CCAATACTTGTCTTAG 36899 1157135 2164 2179 2364 2379 ACTTCCCCTTCTAGCT 64 900 1157169 23102325 2510 2525 GTTACGAAAGTCCTTC 55 901 1157201 2370 2385 2570 2585ACTCAAAGTCCAATGC 69 902 1157235 2495 2510 2695 2710 ATCAAACACTGGTTCC 52903 1157269 2579 2594 2779 2794 CACCAAATCGCACTGG 107 904 1157302 26932708 2893 2908 AAGCCAAGCCGCCTGC 71 905 1157336 2784 2799 2984 2999CCACTCGCTTTCCCTG 59 906 1157370 2844 2859 3044 3059 GGTTACCATAAGTAAG 63907 1157404 2925 2940 3125 3140 CGGAAATCGGCCTACG 70 908 1157437 30063021 3206 3221 TCCAGGACTTGGCAGT 77 909 1157469 3144 3159 3344 3359ATACTTCATTACCCCA 50 910 1157503 3246 3261 3446 3461 CTGAAAACTCCCCCCC 102911 1157536 3371 3386 3571 3586 TATCCTGATATTGGAT 76 912 1157569 34703485 3670 3685 AGTAACTACCAGCCAT 55 913 1157602 3644 3659 3844 3859ACCCAGTTTGTCAATA 90 914 1157635 3731 3746 3931 3946 CAACTGGGAATACTCT 80915 1157669 3896 3911 4096 4111 TGCCAACTAATTGCCA 77 916 1157702 39914006 4191 4206 CTAAGACTTTAAGTTC 73 917 1157736 4109 4124 4309 4324ACCCAGTGGCTCATAT 84 918 1157769 4219 4234 4419 4434 ACCAACCCCCAGTTCA 72919 1157802 4351 4366 4551 4566 GCAGTTTCTATAGTAG 55 920 1157836 45174532 4716 4731 GCATACCTTAACATCT 46 921 1157869 4688 4703 4887 4902ACTCAGAAGATGTTAT 70 922 1157901 4785 4800 4984 4999 GGAGGTATGACATATA 32923 1157935 4838 4853 5037 5052 AGATAATGTTCTCATC 89 924 1157969 49304945 5129 5144 GTTATAGCTTGACAAG 43 925 1158003 5075 5090 5274 5289CATTTATTTCGGCTTC 34 926 1158035 5154 5169 5353 5368 AAGAGATACCTGTCTG 78927 1158069 5244 5259 5443 5458 CAATACTGCAGATGCA 48 928 1158102 53345349 5533 5548 AATCCCCTAGGGAAGG 95 929 1158134 5414 5429 5613 5628GTACTATCCCATCACT 67 930 1158167 5517 5532 5716 5731 GAGATTCAATGCTAAA 42931 1158201 5727 5742 5926 5941 CAAGATTGCCCCAACA 88 932 1158234 57935808 5992 6007 CCTGATCTGGTCCATT 56 933 1158266 5911 5926 6110 6125TTCCTTATTTAGAGGG 86 934 1158300 6007 6022 6206 6221 CACTGTCAATTTATAG 81935 1158334 6097 6112 6296 6311 ATAGTGTAAAACATTG 100 936 1158400 63786393 6577 6592 GTCAAGACAACTGCAT 97 937 1158434 6449 6464 6648 6663CAATGCATTCTAATAG 82 938 1158466 6580 6595 6779 6794 AATACGACTGCTTAAA 70939 1158499 6738 6753 6937 6952 TCTTGAAGACTGTTGC 56 940 1158530 69927007 7191 7206 GTCTGAAGAATACCAT 53 941 1158563 7094 7109 7293 7308TCCCATAACTGATCTG 69 942 1158595 7236 7251 7435 7450 CTTCGGTGCCTTTAGT 77943 1158629 7331 7346 7530 7545 ATCAGGTGAGGCTGAC 77 944 1158662 74587473 7657 7672 TTATTAAGAGCTGCTA 73 945 1158696‡ 7548 7563 7747 7762TTAACAGGCTTCTGGA 56 946 1158730 7665 7680 7864 7879 GCCCACAAGGATCCAA 85947 1158764 7722 7737 7921 7936 GTTCAACCCACCAAAG 64 948 1158796 77987813 7997 8012 ATAGAGCTACTTAGCT 81 949 1158829 7892 7907 8091 8106AGTTACATGTTCCCAC 67 950 1158863 8005 8020 8204 8219 GCTAGCTTGGCCAAGT 98951 1158896 8080 8095 8279 8294 CGTGTTGTTTTCTCAG 77 952 1158927 82678282 8466 8481 AACTAGCACCTGCAGA 83 953 1158961 8348 8363 8547 8562GCTCCTGACAAATTAT 83 954 1158994 8492 8507 8691 8706 TAGAGCTTCTCCATTT 115955

TABLE 43 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: NO: NO: 1 NO: 1 2824 2824 Compound Start Stop StartStop MALAT1 SEQ ID Number Site Site Site Site Sequence (5′ to 3′)(% UTC) No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC 127 18 559497 3629 3644 3829 3844 AGTACTATAGCATCTG 141 32  559564 2839 28543039 3054 CCATAAGTAAGTTCCA 60 36  946424 8006 8021 8205 8220TGCTAGCTTGGCCAAG 84 956 1156461 24 39 N/A N/A TTTACAGAAGTCTCGG 131 9571156494 209 224 175 190 GACAGCTAAGATAGCA 88 958 1156527 317 332 283 298ACCGGAGCAGGAAGAA 96 959 1156561 418 433 384 399 ACCCAGAAGTGTTTAC 84 9601156595 503 518 469 484 TCAAGTGGCCTTTTAA 138 961 1156629 568 583 534 549ACCGTTTTTCAGCTTC 130 962 1156663 625 640 591 606 TGATCTGCGGCCCCCC 150963 1156696 763 778 729 744 AAATCGGAGCAGCACG 84 964 1156730 846 861 812827 AAATGGCGGACTTTCT 83 965 1156764 908 923 874 889 AGGGCTTTACTTTCCA 105966 1156798 971 986 937 952 TCTCTTGAGGGACAGT 107 967 1156832 N/A N/A1047 1062 GCTGCAAACTTTAGAC 109 968 1156866 N/A N/A 1174 1189AAGTAGTTCTTCGGTT 90 969 1156900 1029 1044 1229 1244 CAACTCGCATCACCGG 91970 1156934 1091 1106 1291 1306 CTGCGCTGGCTGCCTC 70 971 1156968 12071222 1407 1422 TCTTAGTAACCTATTG 81 972 1157002 1417 1432 1617 1632TATTGGTATTAATTCG 87 973 1157035 1536 1551 1736 1751 CTTCGGTTTAATCTCT 27974 1157068 1647 1662 1847 1862 TACCACTCCCAATTAA 88 975 1157102 19551970 2155 2170 TCCAATACTTGTCTTA 32 976 1157136 2169 2184 2369 2384AACCAACTTCCCCTTC 84 977 1157170 2311 2326 2511 2526 CGTTACGAAAGTCCTT 75978 1157202 2375 2390 2575 2590 TCTTAACTCAAAGTCC 61 979 1157236 24962511 2696 2711 CATCAAACACTGGTTC 86 980 1157270 2580 2595 2780 2795TCACCAAATCGCACTG 80 981 1157303 2695 2710 2895 2910 CCAAGCCAAGCCGCCT 95982 1157337 2785 2800 2985 3000 ACCACTCGCTTTCCCT 65 983 1157371 28452860 3045 3060 AGGTTACCATAAGTAA 90 984 1157405 2926 2941 3126 3141CCGGAAATCGGCCTAC 80 985 1157438 3014 3029 3214 3229 ACTATTTCTCCAGGAC 80986 1157470 3145 3160 3345 3360 AATACTTCATTACCCC 55 987 1157504 32473262 3447 3462 ACTGAAAACTCCCCCC 103 988 1157537 3372 3387 3572 3587TTATCCTGATATTGGA 112 989 1157570 3471 3486 3671 3686 GAGTAACTACCAGCCA 63990 1157603 3647 3662 3847 3862 CTAACCCAGTTTGTCA 65 991 1157636 37323747 3932 3947 TCAACTGGGAATACTC 83 992 1157670 3897 3912 4097 4112CTGCCAACTAATTGCC 132 993 1157703 3996 4011 4196 4211 CCATTCTAAGACTTTA 51994 1157737 4112 4127 4312 4327 TACACCCAGTGGCTCA 70 995 1157770 42204235 4420 4435 GACCAACCCCCAGTTC 97 996 1157803 4352 4367 4552 4567TGCAGTTTCTATAGTA 91 997 1157837 4518 4533 4717 4732 AGCATACCTTAACATC 81998 1157870 4694 4709 4893 4908 GTTATGACTCAGAAGA 74 999 1157902 47864801 4985 5000 TGGAGGTATGACATAT 41 1000 1157936 4840 4855 5039 5054GCAGATAATGTTCTCA 27 10 1157970 4931 4946 5130 5145 GGTTATAGCTTGACAA 22 91158004 5077 5092 5276 5291 CTCATTTATTTCGGCT 22 1001 1158036 5155 51705354 5369 GAAGAGATACCTGTCT 122 1002 1158070 5245 5260 5444 5459GCAATACTGCAGATGC 119 1003 1158103 5335 5350 5534 5549 AAATCCCCTAGGGAAG108 1004 1158135 5415 5430 5614 5629 TGTACTATCCCATCAC 49 1005 11581685525 5540 5724 5739 AGCCTTCAGAGATTCA 25 1006 1158202 5728 5743 5927 5942CCAAGATTGCCCCAAC 86 1007 1158235 5794 5809 5993 6008 TCCTGATCTGGTCCAT 581008 1158267 5912 5927 6111 6126 ATTCCTTATTTAGAGG 111 1009 1158301 60126027 6211 6226 CTAATCACTGTCAATT 101 1010 1158335 6101 6116 6300 6315GTCAATAGTGTAAAAC 67 1011 1158368 6240 6255 6439 6454 TACACTCACTAGAACA 971012 1158401 6382 6397 6581 6596 TGAAGTCAAGACAACT 99 1013 1158435 64566471 6655 6670 CGTTTCACAATGCATT 53 1014 1158467 6581 6596 6780 6795AAATACGACTGCTTAA 78 1015 1158500 6755 6770 6954 6969 CACTTGCCAGTTTAAT 711016 1158531 6994 7009 7193 7208 TAGTCTGAAGAATACC 77 1017 1158564 70957110 7294 7309 GTCCCATAACTGATCT 65 1018 1158596 7237 7252 7436 7451CCTTCGGTGCCTTTAG 88 1019 1158630 7332 7347 7531 7546 AATCAGGTGAGGCTGA126 1020 1158663 7460 7475 7659 7674 TATTATTAAGAGCTGC 106 1021 1158697‡7552 7567 7751 7766 GCTTTTAACAGGCTTC 67 1022 1158731 7667 7682 7866 7881ATGCCCACAAGGATCC 67 1023 1158765 7724 7739 7923 7938 TAGTTCAACCCACCAA114 1024 1158797 7800 7815 7999 8014 TAATAGAGCTACTTAG 116 1025 11588307893 7908 8092 8107 AAGTTACATGTTCCCA 61 1026 1158897 8094 8109 8293 8308CTGAGAAAACAATACG 92 1027 1158928 8268 8283 8467 8482 GAACTAGCACCTGCAG 961028 1158962 8349 8364 8548 8563 AGCTCCTGACAAATTA 85 1029 1158995 84968511 N/A N/A AATTTAGAGCTTCTCC 79 1030

TABLE 44 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: NO: NO: 1 NO: 1 2824 2824 Compound Start Stop StartStop MALAT1 SEQ ID Number Site Site Site Site Sequence (5′ to 3′)(% UTC) No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC 101 18 559497 3629 3644 3829 3844 AGTACTATAGCATCTG 135 32  559564 2839 28543039 3054 CCATAAGTAAGTTCCA 55 36  946404 2312 2327 2512 2527CCGTTACGAAAGTCCT 33 1031  946410 4113 4128 4313 4328 GTACACCCAGTGGCTC 941032 1156462 25 40 N/A N/A CTTTACAGAAGTCTCG 78 1033 1156495 210 225 176191 GGACAGCTAAGATAGC 78 1034 1156528 318 333 284 299 AACCGGAGCAGGAAGA116 1035 1156562 419 434 385 400 CACCCAGAAGTGTTTA 104 1036 1156596 505520 471 486 GTTCAAGTGGCCTTTT 78 1037 1156630 569 584 535 550TACCGTTTTTCAGCTT 131 1038 1156664 627 642 593 608 TCTGATCTGCGGCCCC 1181039 1156697 764 779 730 745 GAAATCGGAGCAGCAC 99 1040 1156731 847 862813 828 AAAATGGCGGACTTTC 70 1041 1156765 909 924 875 890CAGGGCTTTACTTTCC 98 1042 1156799 978 993 944 959 CTTGTGTTCTCTTGAG 871043 1156833 N/A N/A 1048 1063 AGCTGCAAACTTTAGA 74 1044 1156867 N/A N/A1175 1190 AAAGTAGTTCTTCGGT 83 1045 1156901 1030 1045 1230 1245ACAACTCGCATCACCG 312 1046 1156935 1095 1110 1295 1310 GCCCCTGCGCTGGCTG88 1047 1156969 1208 1223 1408 1423 ATCTTAGTAACCTATT 83 1048 11570031418 1433 1618 1633 CTATTGGTATTAATTC 93 1049 1157036 1537 1552 1737 1752CCTTCGGTTTAATCTC 39 1050 1157069 1649 1664 1849 1864 CCTACCACTCCCAATT 791051 1157103 1956 1971 2156 2171 CTCCAATACTTGTCTT 46 1052 1157137 21702185 2370 2385 TAACCAACTTCCCCTT 84 1053 1157203 2376 2391 2576 2591ATCTTAACTCAAAGTC 61 1054 1157237 2497 2512 2697 2712 TCATCAAACACTGGTT 641055 1157271 2581 2596 2781 2796 TTCACCAAATCGCACT 71 1056 1157304 26962711 2896 2911 GCCAAGCCAAGCCGCC 86 1057 1157338 2786 2801 2986 3001AACCACTCGCTTTCCC 59 1058 1157372 2846 2861 3046 3061 AAGGTTACCATAAGTA 541059 1157406 2927 2942 3127 3142 CCCGGAAATCGGCCTA 100 1060 1157439 30163031 3216 3231 CTACTATTTCTCCAGG 59 1061 1157471 3146 3161 3346 3361AAATACTTCATTACCC 76 1062 1157505 3248 3263 3448 3463 TACTGAAAACTCCCCC 781063 1157538 3373 3388 3573 3588 ATTATCCTGATATTGG 54 1064 1157571 34723487 3672 3687 AGAGTAACTACCAGCC 45 1065 1157604 3648 3663 3848 3863TCTAACCCAGTTTGTC 69 1066 1157637 3733 3748 3933 3948 TTCAACTGGGAATACT 831067 1157671 3899 3914 4099 4114 CACTGCCAACTAATTG 61 1068 1157704 40254040 4225 4240 ACTTGGAAGTTGATAT 96 1069 1157771 4221 4236 4421 4436AGACCAACCCCCAGTT 100 1070 1157804 4353 4368 4553 4568 CTGCAGTTTCTATAGT78 1071 1157838 4520 4535 4719 4734 GAAGCATACCTTAACA 95 1072 11578714695 4710 4894 4909 GGTTATGACTCAGAAG 42 1073 1157903 4787 4802 4986 5001ATGGAGGTATGACATA 80 1074 1157937 4846 4861 5045 5060 GCATATGCAGATAATG 641075 1157971 4932 4947 5131 5146 TGGTTATAGCTTGACA 18 1076 1158005 50785093 5277 5292 TCTCATTTATTTCGGC 21 1077 1158037 5156 5171 5355 5370CGAAGAGATACCTGTC 77 1078 1158071 5246 5261 5445 5460 TGCAATACTGCAGATG 801079 1158104 5336 5351 5535 5550 GAAATCCCCTAGGGAA 94 1080 1158136 54165431 5615 5630 GTGTACTATCCCATCA 52 1081 1158169 5534 5549 5733 5748CTTTCATAGAGCCTTC 57 1082 1158203 5729 5744 5928 5943 CCCAAGATTGCCCCAA107 1083 1158236 5796 5811 5995 6010 AATCCTGATCTGGTCC 54 1084 11582685929 5944 6128 6143 TGTCTAAGAGGTTATT 90 1085 1158302 6013 6028 6212 6227TCTAATCACTGTCAAT 68 1086 1158336 6102 6117 6301 6316 GGTCAATAGTGTAAAA 571087 1158369 6243 6258 6442 6457 TCATACACTCACTAGA 122 1088 1158402 63836398 6582 6597 CTGAAGTCAAGACAAC 117 1089 1158436 6470 6485 6669 6684AATCATACTCCAGTCG 65 1090 1158468 6583 6598 6782 6797 ACAAATACGACTGCTT 841091 1158501 6756 6771 6955 6970 CCACTTGCCAGTTTAA 71 1092 1158532 69977012 7196 7211 CTATAGTCTGAAGAAT 78 1093 1158565 7100 7115 7299 7314CTATTGTCCCATAACT 62 1094 1158597 7238 7253 7437 7452 GCCTTCGGTGCCTTTA102 1095 1158631 7354 7369 7553 7568 GCAAGTCCTCATTACT 50 1096 11586647466 7481 7665 7680 GGGCTTTATTATTAAG 124 1097 1158698‡ 7562 7577 77617776 GGGAGACCTTGCTTTT 79 1098 1158732 7674 7689 7873 7888ATGGATCATGCCCACA 88 1099 1158766 7725 7740 7924 7939 ATAGTTCAACCCACCA 791100 1158798 7801 7816 8000 8015 ATAATAGAGCTACTTA 81 1101 1158831 78947909 8093 8108 CAAGTTACATGTTCCC 58 1102 1158864 8008 8023 8207 8222GATGCTAGCTTGGCCA 102 1103 1158898 8164 8179 8363 8378 CAGGAGTGCCAACCAC102 1104 1158929 8269 8284 8468 8483 AGAACTAGCACCTGCA 85 1105 11589638353 8368 8552 8567 GTCAAGCTCCTGACAA 67 1106 1158996 8497 8512 N/A N/ACAATTTAGAGCTTCTC 112 1107

TABLE 45 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ SEQ NO: NO: ID NO: ID NO: 2824 2824 Compound 1 Start 1 Stop StartStop MALAT1 SEQ Number Site Site Site Site Sequence (5′ to 3′) (% UTC)ID No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC 106 18  5560745797 5812 5996 6011 AAATCCTGATCTGGTC 73 1108  556090 6471 6486 6670 6685TAATCATACTCCAGTC 103 1109  559497 3629 3644 3829 3844 AGTACTATAGCATCTG128 32  559564 2839 2854 3039 3054 CCATAAGTAAGTTCCA 51 36  568476 53385353 5537 5552 CTGAAATCCCCTAGGG 70 1110 1156463 28 43 N/A N/AGTCCTTTACAGAAGTC 65 1111 1156496 213 228 179 194 TAAGGACAGCTAAGAT 761112 1156529 319 334 285 300 GAACCGGAGCAGGAAG 72 1113 1156563 421 436387 402 CACACCCAGAAGTGTT 87 1114 1156597 507 522 473 488GAGTTCAAGTGGCCTT 83 1115 1156631 571 586 537 552 TCTACCGTTTTTCAGC 741116 1156665 628 643 594 609 CTCTGATCTGCGGCCC 106 1117 1156698 765 780731 746 AGAAATCGGAGCAGCA 91 1118 1156732 848 863 814 829CAAAATGGCGGACTTT 83 1119 1156766 916 931 882 897 GATAGTTCAGGGCTTT 901120 1156800 990 1005 956 971 CTTAAAGCACTTCTTG 134 1121 1156834 N/A N/A1054 1069 GATTTGAGCTGCAAAC 100 1122 1156868 N/A N/A 1176 1191AAAAGTAGTTCTTCGG 82 1123 1156902 1031 1046 1231 1246 AACAACTCGCATCACC 831124 1156936 1098 1113 1298 1313 GAAGCCCCTGCGCTGG 77 1125 1156970 12091224 1409 1424 TATCTTAGTAACCTAT 79 1126 1157004 1421 1436 1621 1636CTTCTATTGGTATTAA 82 1127 1157037 1539 1554 1739 1754 CACCTTCGGTTTAATC 801128 1157070 1650 1665 1850 1865 TCCTACCACTCCCAAT 70 1129 1157104 19621977 2162 2177 ATACTTCTCCAATACT 115 1130 1157138 2171 2186 2371 2386TTAACCAACTTCCCCT 57 1131 1157171 2313 2328 2513 2528 TCCGTTACGAAAGTCC 361132 1157204 2401 2416 2601 2616 GCTAGTCCTCAGGATT 53 1133 1157238 25012516 2701 2716 AGCTTCATCAAACACT 97 1134 1157272 2582 2597 2782 2797CTTCACCAAATCGCAC 113 1135 1157305 2697 2712 2897 2912 TGCCAAGCCAAGCCGC87 1136 1157339 2788 2803 2988 3003 CCAACCACTCGCTTTC 74 1137 11573732847 2862 3047 3062 AAAGGTTACCATAAGT 95 1138 1157407 2928 2943 3128 3143ACCCGGAAATCGGCCT 106 1139 1157440 3021 3036 3221 3236 GCCATCTACTATTTCT62 1140 1157472 3167 3182 3367 3382 GGTCATCTATTCACAA 71 1141 11575063249 3264 3449 3464 ATACTGAAAACTCCCC 86 1142 1157539 3374 3389 3574 3589GATTATCCTGATATTG 96 1143 1157572 3473 3488 3673 3688 AAGAGTAACTACCAGC 941144 1157605 3649 3664 3849 3864 CTCTAACCCAGTTTGT 64 1145 1157638 37343749 3934 3949 CTTCAACTGGGAATAC 93 1146 1157672 3907 3922 4107 4122TAACAGGCCACTGCCA 89 1147 1157705 4026 4041 4226 4241 AACTTGGAAGTTGATA 811148 1157738 4115 4130 4315 4330 TGGTACACCCAGTGGC 83 1149 1157772 42224237 4422 4437 CAGACCAACCCCCAGT 107 1150 1157805 4355 4370 4555 4570CTCTGCAGTTTCTATA 69 1151 1157839 4521 4536 4720 4735 TGAAGCATACCTTAAC 691152 1157872 4696 4711 4895 4910 TGGTTATGACTCAGAA 52 1153 1157904 47884803 4987 5002 AATGGAGGTATGACAT 95 1154 1157938 4848 4863 5047 5062TGGCATATGCAGATAA 31 1155 1157972 4933 4948 5132 5147 GTGGTTATAGCTTGAC 211156 1158006 5079 5094 5278 5293 CTCTCATTTATTTCGG 41 1157 1158038 51575172 5356 5371 ACGAAGAGATACCTGT 82 1158 1158072 5247 5262 5446 5461ATGCAATACTGCAGAT 99 1159 1158137 5417 5432 5616 5631 AGTGTACTATCCCATC 221160 1158170 5535 5550 5734 5749 CCTTTCATAGAGCCTT 31 1161 1158204 57315746 5930 5945 CCCCCAAGATTGCCCC 89 1162 1158269 5930 5945 6129 6144CTGTCTAAGAGGTTAT 93 1163 1158303 6014 6029 6213 6228 CTCTAATCACTGTCAA 891164 1158337 6103 6118 6302 6317 AGGTCAATAGTGTAAA 43 1165 1158370 62446259 6443 6458 CTCATACACTCACTAG 100 1166 1158403 6384 6399 6583 6598CCTGAAGTCAAGACAA 100 1167 1158469 6584 6599 6783 6798 CACAAATACGACTGCT76 1168 1158502 6776 6791 6975 6990 ACTGAACTGTTTAAAC 94 1169 11585336998 7013 7197 7212 TCTATAGTCTGAAGAA 74 1170 1158566 7102 7117 7301 7316TACTATTGTCCCATAA 78 1171 1158598 7239 7254 7438 7453 AGCCTTCGGTGCCTTT 951172 1158632 7356 7371 7555 7570 AGGCAAGTCCTCATTA 84 1173 1158665 74717486 7670 7685 GATTTGGGCTTTATTA 77 1174 1158699‡ 7577 7592 7776 7791GAGAAGTTGCTTGTGG 45 1175 1158733 7675 7690 7874 7889 TATGGATCATGCCCAC 731176 1158767 7726 7741 7925 7940 CATAGTTCAACCCACC 65 1177 1158799 78027817 8001 8016 TATAATAGAGCTACTT 85 1178 1158832 7895 7910 8094 8109ACAAGTTACATGTTCC 79 1179 1158865 8010 8025 8209 8224 AAGATGCTAGCTTGGC 761180 1158899 8165 8180 8364 8379 CCAGGAGTGCCAACCA 95 1181 1158930 82708285 8469 8484 AAGAACTAGCACCTGC 87 1182 1158964 8354 8369 8553 8568AGTCAAGCTCCTGACA 87 1183 1158997 8500 8515 N/A N/A CAACAATTTAGAGCTT 881184

TABLE 46 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: NO: NO: 1 NO: 1 2824 2824 Compound Start Stop StartStop MALAT1 SEQ Number Site Site Site Site Sequence (5′ to 3′) (% UTC)ID No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC 104 18  5594973629 3644 3829 3844 AGTACTATAGCATCTG 104 32  559564 2839 2854 3039 3054CCATAAGTAAGTTCCA 60 36  567936 5248 5263 5447 5462 CATGCAATACTGCAGA 851185  946414 5339 5354 5538 5553 CCTGAAATCCCCTAGG 104 1186 1156464 30 45N/A N/A CAGTCCTTTACAGAAG 88 1187 1156497 214 229 180 195ATAAGGACAGCTAAGA 92 1188 1156530 320 335 286 301 TGAACCGGAGCAGGAA 951189 1156564 429 444 395 410 GTCAGGGACACACCCA 111 1190 1156598 508 523474 489 CGAGTTCAAGTGGCCT 82 1191 1156632 572 587 538 553TTCTACCGTTTTTCAG 90 1192 1156666 629 644 595 610 ACTCTGATCTGCGGCC 871193 1156699 766 781 732 747 GAGAAATCGGAGCAGC 85 1194 1156733 849 864815 830 GCAAAATGGCGGACTT 104 1195 1156767 917 932 883 898TGATAGTTCAGGGCTT 91 1196 1156801 N/A N/A 960 975 ACCTCTTAAAGCACTT 821197 1156835 N/A N/A 1055 1070 AGATTTGAGCTGCAAA 89 1198 1156869 N/A N/A1177 1192 AAAAAGTAGTTCTTCG 84 1199 1156903 1032 1047 1232 1247GAACAACTCGCATCAC 85 1200 1156937 1100 1115 1300 1315 CAGAAGCCCCTGCGCT 971201 1156971 1210 1225 1410 1425 ATATCTTAGTAACCTA 85 1202 1157005 14221437 1622 1637 CCTTCTATTGGTATTA 72 1203 1157038 1540 1555 1740 1755TCACCTTCGGTTTAAT 72 1204 1157071 1651 1666 1851 1866 ATCCTACCACTCCCAA 661205 1157105 1963 1978 2163 2178 TATACTTCTCCAATAC 82 1206 1157139 21812196 2381 2396 GATGTGATTTTTAACC 48 1207 1157172 2314 2329 2514 2529TTCCGTTACGAAAGTC 67 1208 1157205 2402 2417 2602 2617 TGCTAGTCCTCAGGAT 811209 1157239 2504 2519 2704 2719 CCTAGCTTCATCAAAC 102 1210 1157273 25842599 2784 2799 TCCTTCACCAAATCGC 64 1211 1157306 2704 2719 2904 2919GTGTGGTTGCCAAGCC 57 1212 1157340 2790 2805 2990 3005 TACCAACCACTCGCTT 991213 1157374 2870 2885 3070 3085 CCCATTATATTAGAAA 90 1214 1157408 29292944 3129 3144 CACCCGGAAATCGGCC 101 1215 1157441 3022 3037 3222 3237TGCCATCTACTATTTC 81 1216 1157473 3168 3183 3368 3383 AGGTCATCTATTCACA 611217 1157507 3278 3293 3478 3493 ATATTTTGCCCCCACC 98 1218 1157540 33763391 3576 3591 CTGATTATCCTGATAT 67 1219 1157573 3474 3489 3674 3689AAAGAGTAACTACCAG 78 1220 1157606 3650 3665 3850 3865 TCTCTAACCCAGTTTG 841221 1157639 3736 3751 3936 3951 AGCTTCAACTGGGAAT 87 1222 1157673 39083923 4108 4123 GTAACAGGCCACTGCC 86 1223 1157706 4027 4042 4227 4242CAACTTGGAAGTTGAT 90 1224 1157739 4116 4131 4316 4331 CTGGTACACCCAGTGG 961225 1157773 4225 4240 4425 4440 GGCCAGACCAACCCCC 97 1226 1157806 43754390 4575 4590 TCATTAAGCCACTTCC 81 1227 1157840 4522 4537 4721 4736TTGAAGCATACCTTAA 72 1228 1157873 4697 4712 4896 4911 CTGGTTATGACTCAGA 991229 1157905 4790 4805 4989 5004 CCAATGGAGGTATGAC 54 1230 1157939 48504865 5049 5064 TTTGGCATATGCAGAT 76 1231 1157973 4935 4950 5134 5149TTGTGGTTATAGCTTG 32 1232 1158007 5093 5108 5292 5307 TGATCCCAACTCATCT 861233 1158039 5158 5173 5357 5372 AACGAAGAGATACCTG 88 1234 1158138 54185433 5617 5632 AAGTGTACTATCCCAT 49 1235 1158171 5536 5551 5735 5750TCCTTTCATAGAGCCT 44 1236 1158205 5732 5747 5931 5946 CCCCCCAAGATTGCCC 861237 1158237 5798 5813 5997 6012 CAAATCCTGATCTGGT 76 1238 1158270‡ 59315946 6130 6145 CCTGTCTAAGAGGTTA 79 1239 1158304 6015 6030 6214 6229ACTCTAATCACTGTCA 65 1240 1158338 6105 6120 6304 6319 TAAGGTCAATAGTGTA 591241 1158371 6245 6260 6444 6459 TCTCATACACTCACTA 89 1242 1158404 63866401 6585 6600 GACCTGAAGTCAAGAC 101 1243 1158437 6472 6487 6671 6686TTAATCATACTCCAGT 81 1244 1158470 6585 6600 6784 6799 TCACAAATACGACTGC 771245 1158503 6788 6803 6987 7002 GCACTAAAGATCACTG 77 1246 1158534 69997014 7198 7213 TTCTATAGTCTGAAGA 86 1247 1158567 7103 7118 7302 7317ATACTATTGTCCCATA 69 1248 1158599 7241 7256 7440 7455 TAAGCCTTCGGTGCCT 961249 1158633 7357 7372 7556 7571 GAGGCAAGTCCTCATT 89 1250 1158666 74737488 7672 7687 GAGATTTGGGCTTTAT 66 1251 1158700‡ 7578 7593 7777 7792AGAGAAGTTGCTTGTG 67 1252 1158734 7676 7691 7875 7890 TTATGGATCATGCCCA 721253 1158768 7727 7742 7926 7941 ACATAGTTCAACCCAC 82 1254 1158800 78037818 8002 8017 TTATAATAGAGCTACT 96 1255 1158833 7896 7911 8095 8110TACAAGTTACATGTTC 80 1256 1158866 8011 8026 8210 8225 TAAGATGCTAGCTTGG 751257 1158900 8166 8181 8365 8380 ACCAGGAGTGCCAACC 92 1258 1158931 82718286 8470 8485 CAAGAACTAGCACCTG 93 1259 1158965 8355 8370 8554 8569AAGTCAAGCTCCTGAC 96 1260 1158998 8501 8516 N/A N/A ACAACAATTTAGAGCT 891261

TABLE 47 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ NO: NO: NO: 1 ID NO: 2824 2824 SEQ Compound Start 1 StopStart Stop MALAT1 ID Number Site Site Site Site Sequence (5′ to 3′)(% UTC) No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC 105 18 559497 3629 3644 3829 3844 AGTACTATAGCATCTG 137 32  559564 2839 28543039 3054 CCATAAGTAAGTTCCA 54 36  568469 4523 4538 4722 4737TTTGAAGCATACCTTA 101 1262 1156465 33 48 N/A N/A CCCCAGTCCTTTACAG 91 12631156498 215 230 181 196 TATAAGGACAGCTAAG 79 1264 1156531 321 336 287 302CTGAACCGGAGCAGGA 113 1265 1156565 430 445 396 411 AGTCAGGGACACACCC 1161266 1156599 509 524 475 490 GCGAGTTCAAGTGGCC 105 1267 1156633 577 592543 558 AATTTTTCTACCGTTT 89 1268 1156667 630 645 596 611CACTCTGATCTGCGGC 128 1269 1156700 767 782 733 748 CGAGAAATCGGAGCAG 781270 1156734 850 865 816 831 GGCAAAATGGCGGACT 114 1271 1156768 919 934885 900 TGTGATAGTTCAGGGC 112 1272 1156802 N/A N/A 961 976TACCTCTTAAAGCACT 117 1273 1156836 N/A N/A 1056 1071 AAGATTTGAGCTGCAA 1011274 1156870 N/A N/A 1178 1193 CAAAAAGTAGTTCTTC 118 1275 1156904 10331048 1233 1248 AGAACAACTCGCATCA 88 1276 1156938 1102 1117 1302 1317AGCAGAAGCCCCTGCG 101 1277 1156972 1211 1226 1411 1426 AATATCTTAGTAACCT81 1278 1157006 1423 1438 1623 1638 CCCTTCTATTGGTATT 93 1279 11570391541 1556 1741 1756 ATCACCTTCGGTTTAA 60 1280 1157072 1653 1668 1853 1868TCATCCTACCACTCCC 66 1281 1157106 1964 1979 2164 2179 CTATACTTCTCCAATA113 1282 1157140 2193 2208 2393 2408 TAGTAGCTTTTTGATG 69 1283 11571732316 2331 2516 2531 ACTTCCGTTACGAAAG 99 1284 1157206 2403 2418 2603 2618ATGCTAGTCCTCAGGA 120 1285 1157240 2505 2520 2705 2720 TCCTAGCTTCATCAAA93 1286 1157274 2589 2604 2789 2804 TAGCTTCCTTCACCAA 101 1287 11573072705 2720 2905 2920 CGTGTGGTTGCCAAGC 55 1288 1157341 2791 2806 2991 3006TTACCAACCACTCGCT 98 1289 1157375 2871 2886 3071 3086 CCCCATTATATTAGAA106 1290 1157409 2930 2945 3130 3145 ACACCCGGAAATCGGC 92 1291 11574423026 3041 3226 3241 AACTTGCCATCTACTA 118 1292 1157474 3169 3184 33693384 CAGGTCATCTATTCAC 49 1293 1157508 3279 3294 3479 3494CATATTTTGCCCCCAC 85 1294 1157541 3377 3392 3577 3592 TCTGATTATCCTGATA 891295 1157574 3503 3518 3703 3718 TAAAGTCTGATTAAGG 96 1296 1157607 36523667 3852 3867 CTTCTCTAACCCAGTT 85 1297 1157640 3757 3772 3957 3972CTGCACTGTGCTGTAC 105 1298 1157674 3909 3924 4109 4124 CGTAACAGGCCACTGC98 1299 1157707 4028 4043 4228 4243 CCAACTTGGAAGTTGA 69 1300 11577404117 4132 4317 4332 ACTGGTACACCCAGTG 108 1301 1157774 4229 4244 44294444 AGTAGGCCAGACCAAC 96 1302 1157807 4376 4391 4576 4591ATCATTAAGCCACTTC 47 1303 1157874 4698 4713 4897 4912 GCTGGTTATGACTCAG 911304 1157906 4791 4806 4990 5005 CCCAATGGAGGTATGA 77 1305 1157940 48764891 5075 5090 TGGTAGCTTTCATTTG 26 1306 1157974 4938 4953 5137 5152TTTTTGTGGTTATAGC 25 1307 1158008 5094 5109 5293 5308 TTGATCCCAACTCATC 671308 1158040 5159 5174 5358 5373 TAACGAAGAGATACCT 78 1309 1158073 52495264 5448 5463 ACATGCAATACTGCAG 97 1310 1158105 5340 5355 5539 5554TCCTGAAATCCCCTAG 112 1311 1158139 5419 5434 5618 5633 GAAGTGTACTATCCCA28 1312 1158172 5537 5552 5736 5751 TTCCTTTCATAGAGCC 30 1313 11582065733 5748 5932 5947 CCCCCCCAAGATTGCC 116 1314 1158238 5799 5814 59986013 TCAAATCCTGATCTGG 82 1315 1158271‡ 5932 5947 6131 6146ACCTGTCTAAGAGGTT 109 1316 1158305 6016 6031 6215 6230 TACTCTAATCACTGTC85 1317 1158339 6106 6121 6305 6320 ATAAGGTCAATAGTGT 62 1318 11583726246 6261 6445 6460 GTCTCATACACTCACT 104 1319 1158405 6388 6403 65876602 CAGACCTGAAGTCAAG 86 1320 1158438 6473 6488 6672 6687TTTAATCATACTCCAG 76 1321 1158471 6586 6601 6785 6800 ATCACAAATACGACTG 661322 1158504 6789 6804 6988 7003 TGCACTAAAGATCACT 63 1323 1158535 70007015 7199 7214 CTTCTATAGTCTGAAG 82 1324 1158568 7105 7120 7304 7319CAATACTATTGTCCCA 53 1325 1158600 7243 7258 7442 7457 TTTAAGCCTTCGGTGC 871326 1158634 7358 7373 7557 7572 TGAGGCAAGTCCTCAT 95 1327 1158667 74767491 7675 7690 CTTGAGATTTGGGCTT 88 1328 1158701‡ 7580 7595 7779 7794GCAGAGAAGTTGCTTG 98 1329 1158735 7677 7692 7876 7891 ATTATGGATCATGCCC 831330 1158769 7728 7743 7927 7942 AACATAGTTCAACCCA 88 1331 1158801 78067821 8005 8020 GTATTATAATAGAGCT 96 1332 1158834 7897 7912 8096 8111CTACAAGTTACATGTT 109 1333 1158867 8012 8027 8211 8226 CTAAGATGCTAGCTTG126 1334 1158901 8167 8182 8366 8381 AACCAGGAGTGCCAAC 123 1335 11589328272 8287 8471 8486 CCAAGAACTAGCACCT 122 1336 1158966 8357 8372 85568571 TCAAGTCAAGCTCCTG 97 1337 1158999 8502 8517 N/A N/A CACAACAATTTAGAGC117 1338

TABLE 48 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ NO: NO: NO: 1 ID NO: 2824 2824 SEQ Compound Start 1 StopStart Stop MALAT1 ID Number Site Site Site Site Sequence (5′ to 3′)(% UTC) No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC 85 18 559497 3629 3644 3829 3844 AGTACTATAGCATCTG 112 32  559564 2839 28543039 3054 CCATAAGTAAGTTCCA 60 36 1156466 34 49 N/A N/A GCCCCAGTCCTTTACA97 1339 1156499 216 231 182 197 CTATAAGGACAGCTAA 96 1340 1156532 322 337288 303 TCTGAACCGGAGCAGG 81 1341 1156566 434 449 400 415AGCCAGTCAGGGACAC 103 1342 1156600 510 525 476 491 AGCGAGTTCAAGTGGC 731343 1156634 578 593 544 559 AAATTTTTCTACCGTT 103 1344 1156668 633 648599 614 GCCCACTCTGATCTGC 104 1345 1156701 769 784 735 750TTCGAGAAATCGGAGC 111 1346 1156735 851 866 817 832 TGGCAAAATGGCGGAC 811347 1156769 920 935 886 901 GTGTGATAGTTCAGGG 92 1348 1156803 N/A N/A976 991 CCGGAACTTTTAAAAT 87 1349 1156837 N/A N/A 1057 1072AAAGATTTGAGCTGCA 104 1350 1156871 N/A N/A 1180 1195 GGCAAAAAGTAGTTCT 691351 1156905 1034 1049 1234 1249 GAGAACAACTCGCATC 80 1352 1156939 11101125 1310 1325 GCCCCCTCAGCAGAAG 75 1353 1156973 1212 1227 1412 1427CAATATCTTAGTAACC 71 1354 1157007 1424 1439 1624 1639 GCCCTTCTATTGGTAT103 1355 1157040 1542 1557 1742 1757 AATCACCTTCGGTTTA 101 1356 11570731655 1670 1855 1870 TTTCATCCTACCACTC 73 1357 1157107 1971 1986 2171 2186CTATCTTCTATACTTC 76 1358 1157141 2194 2209 2394 2409 TTAGTAGCTTTTTGAT 611359 1157174 2318 2333 2518 2533 TTACTTCCGTTACGAA 108 1360 1157207 24042419 2604 2619 AATGCTAGTCCTCAGG 43 1361 1157241 2506 2521 2706 2721GTCCTAGCTTCATCAA 82 1362 1157275 2591 2606 2791 2806 CCTAGCTTCCTTCACC 831363 1157308 2708 2723 2908 2923 CTCCGTGTGGTTGCCA 76 1364 1157342 27922807 2992 3007 TTTACCAACCACTCGC 82 1365 1157376 2872 2887 3072 3087CCCCCATTATATTAGA 72 1366 1157410 2931 2946 3131 3146 AACACCCGGAAATCGG 741367 1157443 3027 3042 3227 3242 AAACTTGCCATCTACT 104 1368 1157475 31713186 3371 3386 AACAGGTCATCTATTC 67 1369 1157509 3280 3295 3480 3495ACATATTTTGCCCCCA 81 1370 1157542 3378 3393 3578 3593 GTCTGATTATCCTGAT 671371 1157575 3510 3525 3710 3725 GCACTTTTAAAGTCTG 26 1372 1157608 36593674 3859 3874 TACACTCCTTCTCTAA 118 1373 1157641 3764 3779 3964 3979ACCAAAGCTGCACTGT 85 1374 1157675 3910 3925 4110 4125 CCGTAACAGGCCACTG 701375 1157708 4029 4044 4229 4244 GCCAACTTGGAAGTTG 119 1376 1157741 41184133 4318 4333 CACTGGTACACCCAGT 85 1377 1157775 4230 4245 4430 4445CAGTAGGCCAGACCAA 86 1378 1157808 4377 4392 4577 4592 GATCATTAAGCCACTT 901379 1157841 4526 4541 4725 4740 ATTTTTGAAGCATACC 59 1380 1157875 46994714 4898 4913 GGCTGGTTATGACTCA 60 1381 1157907 4792 4807 4991 5006CCCCAATGGAGGTATG 63 1382 1157941 4878 4893 5077 5092 ATTGGTAGCTTTCATT 301383 1157975 4970 4985 5169 5184 GCCTCTTCATTGTATT 90 1384 1158009 50955110 5294 5309 CTTGATCCCAACTCAT 89 1385 1158041 5160 5175 5359 5374ATAACGAAGAGATACC 94 1386 1158074 5251 5266 5450 5465 TAACATGCAATACTGC 821387 1158106 5341 5356 5540 5555 ATCCTGAAATCCCCTA 92 1388 1158140 54205435 5619 5634 TGAAGTGTACTATCCC 28 1389 1158173 5539 5554 5738 5753TATTCCTTTCATAGAG 89 1390 1158207 5734 5749 5933 5948 TCCCCCCCAAGATTGC103 1391 1158239 5800 5815 5999 6014 CTCAAATCCTGATCTG 63 1392 1158272‡5936 5951 6135 6150 TCCCACCTGTCTAAGA 96 1393 1158306 6017 6032 6216 6231TTACTCTAATCACTGT 67 1394 1158340 6107 6122 6306 6321 TATAAGGTCAATAGTG 621395 1158373 6251 6266 6450 6465 GCAAGGTCTCATACAC 52 1396 1158406 64076422 6606 6621 TACTTGCCAACAGAAC 81 1397 1158439 6475 6490 6674 6689CTTTTAATCATACTCC 84 1398 1158472 6587 6602 6786 6801 AATCACAAATACGACT 771399 1158505 6790 6805 6989 7004 ATGCACTAAAGATCAC 66 1400 1158536 70027017 7201 7216 TCCTTCTATAGTCTGA 86 1401 1158569 7106 7121 7305 7320TCAATACTATTGTCCC 34 1402 1158601 7244 7259 7443 7458 CTTTAAGCCTTCGGTG103 1403 1158635 7359 7374 7558 7573 TTGAGGCAAGTCCTCA 97 1404 11586687478 7493 7677 7692 CGCTTGAGATTTGGGC 67 1405 1158702‡ 7583 7598 77827797 GTGGCAGAGAAGTTGC 83 1406 1158736 7678 7693 7877 7892GATTATGGATCATGCC 53 1407 1158770 7729 7744 7928 7943 TAACATAGTTCAACCC 831408 1158802 7807 7822 8006 8021 AGTATTATAATAGAGC 80 1409 1158835 78987913 8097 8112 TCTACAAGTTACATGT 77 1410 1158868 8013 8028 8212 8227GCTAAGATGCTAGCTT 90 1411 1158902 8169 8184 8368 8383 GAAACCAGGAGTGCCA 961412 1158933 8273 8288 8472 8487 TCCAAGAACTAGCACC 105 1413 1158967 83588373 8557 8572 ATCAAGTCAAGCTCCT 89 1414 1159000 8503 8518 N/A N/ACCACAACAATTTAGAG 127 1415

TABLE 49 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ NO: NO: NO: 1 ID NO: 2824 2824 Compound Start 1 Stop StartStop MALAT1 SEQ Number Site Site Site Site Sequence (5′ to 3′) (% UTC)ID No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC 110 18  5594973629 3644 3829 3844 AGTACTATAGCATCTG 134 32  559564 2839 2854 3039 3054CCATAAGTAAGTTCCA 60 36  568454 3028 3043 3228 3243 CAAACTTGCCATCTAC 891416  568459 3516 3531 3716 3731 GGTTAAGCACTTTTAA 62 1417 1156467 52 6718 33 GGAGAGGCCAGTTGCG 110 1418 1156500 217 232 183 198 CCTATAAGGACAGCTA85 1419 1156533 323 338 289 304 TTCTGAACCGGAGCAG 77 1420 1156567 443 458409 424 ACCTTGGGCAGCCAGT 104 1421 1156601 511 526 477 492AAGCGAGTTCAAGTGG 85 1422 1156635 580 595 546 561 GGAAATTTTTCTACCG 921423 1156669 640 655 606 621 GCCAGTGGCCCACTCT 108 1424 1156702 770 785736 751 GTTCGAGAAATCGGAG 85 1425 1156736 852 867 818 833GTGGCAAAATGGCGGA 79 1426 1156770 921 936 887 902 AGTGTGATAGTTCAGG 931427 1156804 N/A N/A 977 992 CCCGGAACTTTTAAAA 107 1428 1156838 N/A N/A1058 1073 GAAAGATTTGAGCTGC 110 1429 1156872 N/A N/A 1183 1198GGAGGCAAAAAGTAGT 91 1430 1156906 1035 1050 1235 1250 GGAGAACAACTCGCAT 831431 1156940 1126 1141 1326 1341 TCCTCAAGCTCCGCCT 77 1432 1156974 12131228 1413 1428 GCAATATCTTAGTAAC 77 1433 1157008 1426 1441 1626 1641TTGCCCTTCTATTGGT 89 1434 1157041 1544 1559 1744 1759 TTAATCACCTTCGGTT 731435 1157074 1659 1674 1859 1874 ATTGTTTCATCCTACC 78 1436 1157108 20082023 2208 2223 CAGTGCTATTTTATCC 22 1437 1157142 2200 2215 2400 2415GTCCTTTTAGTAGCTT 50 1438 1157175 2319 2334 2519 2534 ATTACTTCCGTTACGA 571439 1157208 2405 2420 2605 2620 TAATGCTAGTCCTCAG 62 1440 1157242 25072522 2707 2722 AGTCCTAGCTTCATCA 73 1441 1157276 2631 2646 2831 2846CCTAGCTTCACCACCA 67 1442 1157309 2710 2725 2910 2925 TCCTCCGTGTGGTTGC 821443 1157343 2793 2808 2993 3008 TTTTACCAACCACTCG 69 1444 1157377 28732888 3073 3088 TCCCCCATTATATTAG 86 1445 1157411 2932 2947 3132 3147CAACACCCGGAAATCG 82 1446 1157476 3176 3191 3376 3391 GTAAAAACAGGTCATC 791447 1157510 3281 3296 3481 3496 AACATATTTTGCCCCC 78 1448 1157543 33863401 3586 3601 CTGTGGTGGTCTGATT 67 1449 1157609 3660 3675 3860 3875GTACACTCCTTCTCTA 83 1450 1157642 3767 3782 3967 3982 TGAACCAAAGCTGCAC 981451 1157676 3911 3926 4111 4126 ACCGTAACAGGCCACT 80 1452 1157709 40304045 4230 4245 TGCCAACTTGGAAGTT 68 1453 1157742 4119 4134 4319 4334GCACTGGTACACCCAG 109 1454 1157776 4231 4246 4431 4446 CCAGTAGGCCAGACCA87 1455 1157809 4378 4393 4578 4593 GGATCATTAAGCCACT 85 1456 11578424580 4595 4779 4794 TCTTAATCAGTTACAA 91 1457 1157876 4701 4716 4900 4915CAGGCTGGTTATGACT 74 1458 1157908 4793 4808 4992 5007 TCCCCAATGGAGGTAT 911459 1157942 4879 4894 5078 5093 AATTGGTAGCTTTCAT 36 1460 1157976 49744989 5173 5188 CATTGCCTCTTCATTG 64 1461 1158010 5097 5112 5296 5311CACTTGATCCCAACTC 56 1462 1158042 5161 5176 5360 5375 GATAACGAAGAGATAC 811463 1158075 5252 5267 5451 5466 CTAACATGCAATACTG 99 1464 1158107 53435358 5542 5557 CAATCCTGAAATCCCC 84 1465 1158141 5422 5437 5621 5636AGTGAAGTGTACTATC 56 1466 1158174 5540 5555 5739 5754 CTATTCCTTTCATAGA111 1467 1158208 5735 5750 5934 5949 ATCCCCCCCAAGATTG 95 1468 11582405802 5817 6001 6016 CGCTCAAATCCTGATC 77 1469 1158273 5938 5953 6137 6152TCTCCCACCTGTCTAA 77 1470 1158307 6018 6033 6217 6232 ATTACTCTAATCACTG 721471 1158341 6108 6123 6307 6322 ATATAAGGTCAATAGT 84 1472 1158374 62526267 6451 6466 TGCAAGGTCTCATACA 68 1473 1158407 6409 6424 6608 6623TTTACTTGCCAACAGA 73 1474 1158440 6476 6491 6675 6690 ACTTTTAATCATACTC 791475 1158473 6588 6603 6787 6802 CAATCACAAATACGAC 82 1476 1158506 67926807 6991 7006 CAATGCACTAAAGATC 90 1477 1158537 7009 7024 7208 7223TGGAAGCTCCTTCTAT 119 1478 1158570 7107 7122 7306 7321 TTCAATACTATTGTCC42 1479 1158602 7245 7260 7444 7459 ACTTTAAGCCTTCGGT 87 1480 11586367360 7375 7559 7574 GTTGAGGCAAGTCCTC 97 1481 1158669 7479 7494 7678 7693CCGCTTGAGATTTGGG 72 1482 1158703# 7590 7605 7789 7804 TGGCGATGTGGCAGAG65 1483 1158737 7679 7694 7878 7893 CGATTATGGATCATGC 56 1484 11587717730 7745 7929 7944 CTAACATAGTTCAACC 84 1485 1158803 7814 7829 8013 8028CTGGATAAGTATTATA 72 1486 1158836 7899 7914 8098 8113 GTCTACAAGTTACATG 871487 1158869 8014 8029 8213 8228 CGCTAAGATGCTAGCT 106 1488 1158903 81718186 8370 8385 TGGAAACCAGGAGTGC 86 1489 1158934 8275 8290 8474 8489ACTCCAAGAACTAGCA 89 1490 1158968 8359 8374 8558 8573 AATCAAGTCAAGCTCC 861491 1159001 8504 8519 N/A N/A ACCACAACAATTTAGA 110 1492

TABLE 50 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ NO: NO: NO: 1 ID NO: 2824 2824 Compound Start 1 Stop StartStop MALAT1 SEQ Number Site Site Site Site Sequence (5′ to 3′) (% UTC)ID No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC 87 18  5594973629 3644 3829 3844 AGTACTATAGCATCTG 119 32  559564 2839 2854 3039 3054CCATAAGTAAGTTCCA 36 36 1156468 64 79 30 45 CTTAAGAGGGCAGGAG 104 14931156501 218 233 184 199 GCCTATAAGGACAGCT 89 1494 1156534 324 339 290 305CTTCTGAACCGGAGCA 127 1495 1156568 456 471 422 437 CGAAGACACAGAGACC 901496 1156602 512 527 478 493 AAAGCGAGTTCAAGTG 112 1497 1156636 581 596547 562 CGGAAATTTTTCTACC 92 1498 1156670 649 664 615 630CCGTTGGCTGCCAGTG 94 1499 1156703 771 786 737 752 TGTTCGAGAAATCGGA 831500 1156737 860 875 826 841 GTTGAGAAGTGGCAAA 80 1501 1156771 924 939890 905 TAAAGTGTGATAGTTC 86 1502 1156805 N/A N/A 978 993CCCCGGAACTTTTAAA 77 1503 1156839 N/A N/A 1061 1076 GTGGAAAGATTTGAGC 831504 1156873 N/A N/A 1190 1205 TTGTGAGGGAGGCAAA 80 1505 1156907 10361051 1236 1251 CGGAGAACAACTCGCA 104 1506 1156941 1128 1143 1328 1343TTTCCTCAAGCTCCGC 46 1507 1156975 1216 1231 1416 1431 TAAGCAATATCTTAGT 841508 1157009 1429 1444 1629 1644 GCATTGCCCTTCTATT 30 1509 1157042 15451560 1745 1760 TTTAATCACCTTCGGT 34 1510 1157075 1663 1678 1863 1878CCAAATTGTTTCATCC 37 1511 1157109 2009 2024 2209 2224 TCAGTGCTATTTTATC 261512 1157143 2202 2217 2402 2417 CAGTCCTTTTAGTAGC 43 1513 1157176 23202335 2520 2535 AATTACTTCCGTTACG 57 1514 1157209 2406 2421 2606 2621TTAATGCTAGTCCTCA 61 1515 1157243 2508 2523 2708 2723 CAGTCCTAGCTTCATC 911516 1157277 2632 2647 2832 2847 TCCTAGCTTCACCACC 56 1517 1157310 27122727 2912 2927 CCTCCTCCGTGTGGTT 68 1518 1157344 2794 2809 2994 3009TTTTTACCAACCACTC 74 1519 1157378 2874 2889 3074 3089 CTCCCCCATTATATTA 691520 1157412 2934 2949 3134 3149 TACAACACCCGGAAAT 84 1521 1157444 30293044 3229 3244 ACAAACTTGCCATCTA 61 1522 1157477 3189 3204 3389 3404TCAGGGTGAGGAAGTA 50 1523 1157511 3308 3323 3508 3523 GACAGACCTAAGGGAA 661524 1157544 3387 3402 3587 3602 CCTGTGGTGGTCTGAT 46 1525 1157576 35173532 3717 3732 GGGTTAAGCACTTTTA 43 1526 1157610 3662 3677 3862 3877CGGTACACTCCTTCTC 60 1527 1157643 3769 3784 3969 3984 TATGAACCAAAGCTGC 931528 1157677 3912 3927 4112 4127 AACCGTAACAGGCCAC 50 1529 1157710 40344049 4234 4249 TACTTGCCAACTTGGA 49 1530 1157743 4121 4136 4321 4336ATGCACTGGTACACCC 76 1531 1157777 4233 4248 4433 4448 GCCCAGTAGGCCAGAC 751532 1157810 4380 4395 4580 4595 CAGGATCATTAAGCCA 58 1533 1157843 45864601 4785 4800 CACAATTCTTAATCAG 59 1534 1157877 4702 4717 4901 4916CCAGGCTGGTTATGAC 56 1535 1157909 4795 4810 4994 5009 ATTCCCCAATGGAGGT 641536 1157943 4881 4896 5080 5095 TAAATTGGTAGCTTTC 26 1537 1157977 49774992 5176 5191 GGACATTGCCTCTTCA 46 1538 1158011 5098 5113 5297 5312CCACTTGATCCCAACT 53 1539 1158043 5162 5177 5361 5376 TGATAACGAAGAGATA 851540 1158076 5253 5268 5452 5467 CCTAACATGCAATACT 88 1541 1158108 53605375 5559 5574 TCGATGGAAAAATTTC 70 1542 1158142 5423 5438 5622 5637GAGTGAAGTGTACTAT 38 1543 1158175 5541 5556 5740 5755 GCTATTCCTTTCATAG 341544 1158209 5736 5751 5935 5950 AATCCCCCCCAAGATT 105 1545 1158241 58045819 6003 6018 TCCGCTCAAATCCTGA 74 1546 1158274 5939 5954 6138 6153ATCTCCCACCTGTCTA 55 1547 1158308 6020 6035 6219 6234 GTATTACTCTAATCAC 661548 1158342 6109 6124 6308 6323 TATATAAGGTCAATAG 95 1549 1158375 62536268 6452 6467 CTGCAAGGTCTCATAC 76 1550 1158408 6410 6425 6609 6624ATTTACTTGCCAACAG 53 1551 1158441 6485 6500 6684 6699 GGGAACACAACTTTTA 671552 1158474 6589 6604 6788 6803 TCAATCACAAATACGA 70 1553 1158507 67986813 6997 7012 CATAAACAATGCACTA 86 1554 1158538 7010 7025 7209 7224CTGGAAGCTCCTTCTA 75 1555 1158571 7108 7123 7307 7322 ATTCAATACTATTGTC 761556 1158603 7246 7261 7445 7460 TACTTTAAGCCTTCGG 71 1557 1158637 73627377 7561 7576 GAGTTGAGGCAAGTCC 48 1558 1158670 7480 7495 7679 7694ACCGCTTGAGATTTGG 68 1559 1158704‡ 7591 7606 7790 7805 GTGGCGATGTGGCAGA59 1560 1158738 7680 7695 7879 7894 CCGATTATGGATCATG 37 1561 11587727731 7746 7930 7945 TCTAACATAGTTCAAC 71 1562 1158804 7815 7830 8014 8029ACTGGATAAGTATTAT 54 1563 1158837 7900 7915 8099 8114 AGTCTACAAGTTACAT 971564 1158870 8015 8030 8214 8229 CCGCTAAGATGCTAGC 80 1565 1158904 81768191 8375 8390 CGTCCTGGAAACCAGG 79 1566 1158935 8276 8291 8475 8490AACTCCAAGAACTAGC 70 1567 1158969 8360 8375 8559 8574 CAATCAAGTCAAGCTC 971568 1159002 8505 8520 N/A N/A AACCACAACAATTTAG 84 1569

TABLE 51 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: NO: NO: 1 NO: 1 2824 2824 Compound Start Stop StartStop MALAT1 SEQ ID Number Site Site Site Site Sequence (5′ to 3′)(% UTC) No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC 132 18 556131 8177 8192 8376 8391 CCGTCCTGGAAACCAG 84 1570  559497 3629 36443829 3844 AGTACTATAGCATCTG 119 32  559564 2839 2854 3039 3054CCATAAGTAAGTTCCA 49 36  568477 5424 5439 5623 5638 TGAGTGAAGTGTACTA 581571  568491 6831 6846 7030 7045 TTAAGACCAAGGGAGG 71 1572 1156469 65 8031 46 GCTTAAGAGGGCAGGA 107 1573 1156502 219 234 185 200 AGCCTATAAGGACAGC77 1574 1156535 325 340 291 306 CCTTCTGAACCGGAGC 104 1575 1156569 457472 423 438 CCGAAGACACAGAGAC 98 1576 1156603 513 528 479 494GAAAGCGAGTTCAAGT 101 1577 1156637 582 597 548 563 ACGGAAATTTTTCTAC 961578 1156671 650 665 616 631 GCCGTTGGCTGCCAGT 108 1579 1156704 772 787738 753 TTGTTCGAGAAATCGG 95 1580 1156738 862 877 828 843CGGTTGAGAAGTGGCA 111 1581 1156772 925 940 891 906 TTAAAGTGTGATAGTT 941582 1156806 N/A N/A 979 994 CCCCCGGAACTTTTAA 112 1583 1156840 N/A N/A1064 1079 CGTGTGGAAAGATTTG 100 1584 1156874 N/A N/A 1193 1208CCTTTGTGAGGGAGGC 105 1585 1156908 1037 1052 1237 1252 ACGGAGAACAACTCGC99 1586 1156942 1129 1144 1329 1344 GTTTCCTCAAGCTCCG 41 1587 11569761217 1232 1417 1432 CTAAGCAATATCTTAG 85 1588 1157010 1431 1446 1631 1646AAGCATTGCCCTTCTA 54 1589 1157043 1546 1561 1746 1761 TTTTAATCACCTTCGG 561590 1157076 1707 1722 1907 1922 CGTACTTCTGTCTTCC 36 1591 1157110 20332048 2233 2248 GTTACCAATAATTTCC 29 1592 1157144 2204 2219 2404 2419ACCAGTCCTTTTAGTA 102 1593 1157177 2321 2336 2521 2536 GAATTACTTCCGTTAC64 1594 1157210 2407 2422 2607 2622 ATTAATGCTAGTCCTC 64 1595 11572442510 2525 2710 2725 CTCAGTCCTAGCTTCA 58 1596 1157278 2633 2648 2833 2848TTCCTAGCTTCACCAC 64 1597 1157311 2713 2728 2913 2928 GCCTCCTCCGTGTGGT101 1598 1157345 2796 2811 2996 3011 GATTTTTACCAACCAC 58 1599 11573792875 2890 3075 3090 ACTCCCCCATTATATT 98 1600 1157413 2935 2950 3135 3150CTACAACACCCGGAAA 67 1601 1157445 3032 3047 3232 3247 CCCACAAACTTGCCAT 991602 1157478 3194 3209 3394 3409 CGAATTCAGGGTGAGG 32 1603 1157512 33093324 3509 3524 AGACAGACCTAAGGGA 79 1604 1157545 3391 3406 3591 3606TAAACCTGTGGTGGTC 70 1605 1157577 3531 3546 3731 3746 ATAACAAGTTTAAGGG 591606 1157611 3663 3678 3863 3878 GCGGTACACTCCTTCT 72 1607 1157644 37763791 3976 3991 GACTGAATATGAACCA 49 1608 1157678 3913 3928 4113 4128CAACCGTAACAGGCCA 77 1609 1157711 4035 4050 4235 4250 TTACTTGCCAACTTGG 301610 1157744 4123 4138 4323 4338 TAATGCACTGGTACAC 122 1611 1157778 42414256 4441 4456 TAATGTCAGCCCAGTA 93 1612 1157811 4381 4396 4581 4596TCAGGATCATTAAGCC 63 1613 1157844 4591 4606 4790 4805 ACTATCACAATTCTTA 871614 1157878 4705 4720 4904 4919 CTGCCAGGCTGGTTAT 99 1615 1157910 47964811 4995 5010 TATTCCCCAATGGAGG 83 1616 1157944 4884 4899 5083 5098CTTTAAATTGGTAGCT 55 1617 1157978 4978 4993 5177 5192 TGGACATTGCCTCTTC 711618 1158012 5099 5114 5298 5313 TCCACTTGATCCCAAC 53 1619 1158044 51635178 5362 5377 CTGATAACGAAGAGAT 103 1620 1158077 5254 5269 5453 5468CCCTAACATGCAATAC 86 1621 1158109 5361 5376 5560 5575 CTCGATGGAAAAATTT 921622 1158176 5550 5565 5749 5764 GCACATCATGCTATTC 55 1623 1158210 57375752 5936 5951 GAATCCCCCCCAAGAT 115 1624 1158242 5805 5820 6004 6019TTCCGCTCAAATCCTG 65 1625 1158275 5941 5956 6140 6155 TAATCTCCCACCTGTC 931626 1158309 6021 6036 6220 6235 AGTATTACTCTAATCA 77 1627 1158343 61106125 6309 6324 CTATATAAGGTCAATA 84 1628 1158376 6254 6269 6453 6468ACTGCAAGGTCTCATA 101 1629 1158409 6412 6427 6611 6626 GCATTTACTTGCCAAC89 1630 1158442 6499 6514 6698 6713 TACTCCAAGCATTGGG 100 1631 11584756590 6605 6789 6804 TTCAATCACAAATACG 81 1632 1158539 7012 7027 7211 7226AACTGGAAGCTCCTTC 83 1633 1158572 7115 7130 7314 7329 GAAATCTATTCAATAC 761634 1158604 7247 7262 7446 7461 CTACTTTAAGCCTTCG 69 1635 1158638 73637378 7562 7577 GGAGTTGAGGCAAGTC 59 1636 1158671 7481 7496 7680 7695CACCGCTTGAGATTTG 53 1637 1158705‡ 7607 7622 7806 7821 GATCAAAAGGCACGGG70 1638 1158739 7681 7696 7880 7895 ACCGATTATGGATCAT 64 1639 11587737736 7751 7935 7950 CCTTTTCTAACATAGT 77 1640 1158805 7816 7831 8015 8030CACTGGATAAGTATTA 60 1641 1158838 7901 7916 8100 8115 CAGTCTACAAGTTACA 731642 1158871 8016 8031 8215 8230 TCCGCTAAGATGCTAG 85 1643 1158936‡ 82998314 8498 8513 GCTGTTACCTCCCACC 74 1644 1158970 8361 8376 8560 8575ACAATCAAGTCAAGCT 85 1645 1159003 8506 8521 N/A N/A GAACCACAACAATTTA 811646

TABLE 52 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: NO: NO: 1 NO: 1 2824 2824 Compound Start Stop StartStop MALAT1 SEQ ID Number Site Site Site Site Sequence (5′ to 3′)(% UTC) No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC 116 18 559497 3629 3644 3829 3844 AGTACTATAGCATCTG 116 32  559564 2839 28543039 3054 CCATAAGTAAGTTCCA 36 36  946398 66 81 32 47 CGCTTAAGAGGGCAGG 881647  946402 1435 1450 1635 1650 CTAAAAGCATTGCCCT 65 1648  946413 51005115 5299 5314 ATCCACTTGATCCCAA 84 1649 1156503 220 235 186 201CAGCCTATAAGGACAG 78 1650 1156536 326 341 292 307 ACCTTCTGAACCGGAG 781651 1156570 459 474 425 440 CTCCGAAGACACAGAG 103 1652 1156604 514 529480 495 GGAAAGCGAGTTCAAG 76 1653 1156638 583 598 549 564CACGGAAATTTTTCTA 92 1654 1156672 651 666 617 632 GGCCGTTGGCTGCCAG 791655 1156705 775 790 741 756 TTTTTGTTCGAGAAAT 107 1656 1156739 863 878829 844 ACGGTTGAGAAGTGGC 78 1657 1156773 926 941 892 907ATTAAAGTGTGATAGT 83 1658 1156807 N/A N/A 980 995 ACCCCCGGAACTTTTA 911659 1156841 N/A N/A 1078 1093 ACTTAAATTACTAGCG 110 1660 1156875 N/A N/A1194 1209 GCCTTTGTGAGGGAGG 123 1661 1156909 1039 1054 1239 1254AGACGGAGAACAACTC 114 1662 1156943 1130 1145 1330 1345 GGTTTCCTCAAGCTCC66 1663 1156977 1218 1233 1418 1433 GCTAAGCAATATCTTA 68 1664 11570441547 1562 1747 1762 CTTTTAATCACCTTCG 26 1665 1157077 1708 1723 1908 1923CCGTACTTCTGTCTTC 36 1666 1157111※ 2034 2049 2234 2249 GGTTACCAATAATTTC11 3 1157145 2208 2223 2408 2423 TTACACCAGTCCTTTT 63 1667 1157178 23222337 2522 2537 TGAATTACTTCCGTTA 64 1668 1157211 2408 2423 2608 2623AATTAATGCTAGTCCT 84 1669 1157245 2515 2530 2715 2730 TGCTCCTCAGTCCTAG 741670 1157279 2635 2650 2835 2850 TTTTCCTAGCTTCACC 33 1671 1157312 27152730 2915 2930 TCGCCTCCTCCGTGTG 67 1672 1157346 2797 2812 2997 3012GGATTTTTACCAACCA 86 1673 1157380 2876 2891 3076 3091 AACTCCCCCATTATAT101 1674 1157414 2936 2951 3136 3151 CCTACAACACCCGGAA 100 1675 11574463033 3048 3233 3248 ACCCACAAACTTGCCA 102 1676 1157479 3197 3212 33973412 AAACGAATTCAGGGTG 77 1677 1157513 3311 3326 3511 3526CTAGACAGACCTAAGG 98 1678 1157546 3392 3407 3592 3607 GTAAACCTGTGGTGGT 441679 1157578 3559 3574 3759 3774 GACCATCCCAAAATGC 92 1680 1157612 36643679 3864 3879 AGCGGTACACTCCTTC 50 1681 1157645 3777 3792 3977 3992TGACTGAATATGAACC 59 1682 1157679 3914 3929 4114 4129 CCAACCGTAACAGGCC 731683 1157712 4036 4051 4236 4251 GTTACTTGCCAACTTG 37 1684 1157745 41244139 4324 4339 TTAATGCACTGGTACA 78 1685 1157779 4242 4257 4442 4457TTAATGTCAGCCCAGT 63 1686 1157812 4382 4397 4582 4597 TTCAGGATCATTAAGC 821687 1157845 4593 4608 4792 4807 GAACTATCACAATTCT 97 1688 1157879 47104725 4909 4924 TCATACTGCCAGGCTG 71 1689 1157911 4797 4812 4996 5011TTATTCCCCAATGGAG 82 1690 1157945 4885 4900 5084 5099 ACTTTAAATTGGTAGC 721691 1157979 4979 4994 5178 5193 ATGGACATTGCCTCTT 63 1692 1158045 51645179 5363 5378 TCTGATAACGAAGAGA 79 1693 1158078 5255 5270 5454 5469TCCCTAACATGCAATA 70 1694 1158110 5362 5377 5561 5576 GCTCGATGGAAAAATT 901695 1158143 5425 5440 5624 5639 CTGAGTGAAGTGTACT 52 1696 1158177 55515566 5750 5765 AGCACATCATGCTATT 74 1697 1158211 5739 5754 5938 5953AAGAATCCCCCCCAAG 72 1698 1158243 5807 5822 6006 6021 TCTTCCGCTCAAATCC 591699 1158276 5942 5957 6141 6156 ATAATCTCCCACCTGT 83 1700 1158310 60226037 6221 6236 AAGTATTACTCTAATC 91 1701 1158344 6112 6127 6311 6326CCCTATATAAGGTCAA 87 1702 1158377 6255 6270 6454 6469 CACTGCAAGGTCTCAT 591703 1158410 6414 6429 6613 6628 CTGCATTTACTTGCCA 83 1704 1158443 65006515 6699 6714 CTACTCCAAGCATTGG 73 1705 1158476 6593 6608 6792 6807AGCTTCAATCACAAAT 77 1706 1158508 6834 6849 7033 7048 GAATTAAGACCAAGGG 641707 1158540 7013 7028 7212 7227 CAACTGGAAGCTCCTT 77 1708 1158573 71187133 7317 7332 GCTGAAATCTATTCAA 259 1709 1158605 7248 7263 7447 7462CCTACTTTAAGCCTTC 65 1710 1158639 7364 7379 7563 7578 GGGAGTTGAGGCAAGT 941711 1158672 7483 7498 7682 7697 AGCACCGCTTGAGATT 58 1712 1158706‡ 76087623 7807 7822 AGATCAAAAGGCACGG 80 1713 1158740 7682 7697 7881 7896AACCGATTATGGATCA 51 1714 1158774 7737 7752 7936 7951 GCCTTTTCTAACATAG101 1715 1158806 7818 7833 8017 8032 GTCACTGGATAAGTAT 52 1716 11588397902 7917 8101 8116 CCAGTCTACAAGTTAC 50 1717 1158872 8017 8032 8216 8231TTCCGCTAAGATGCTA 91 1718 1158905 8179 8194 8378 8393 CCCCGTCCTGGAAACC 791719 1158937 8300 8315 8499 8514 TGCTGTTACCTCCCAC 86 1720 1158971 83628377 8561 8576 TACAATCAAGTCAAGC 102 1721 1159004 8535 8550 N/A N/ACCCCAATCAAGATTTT 121 1722

TABLE 53 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: NO: NO: 1 NO: 1 2824 2824 Compound Start Stop StartStop MALAT1 SEQ ID Number Site Site Site Site Sequence (5′ to 3′)(% UTC) No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC 105 18 559497 3629 3644 3829 3844 AGTACTATAGCATCTG 117 32  559564 2839 28543039 3054 CCATAAGTAAGTTCCA 45 36  946406 2937 2952 3137 3152ACCTACAACACCCGGA 75 1723 1156470 67 82 33 48 GCGCTTAAGAGGGCAG 94 17241156504 221 236 187 202 CCAGCCTATAAGGACA 101 1725 1156537 329 344 295310 CAGACCTTCTGAACCG 90 1726 1156571 460 475 426 441 TCTCCGAAGACACAGA100 1727 1156605 515 530 481 496 TGGAAAGCGAGTTCAA 104 1728 1156639 584599 550 565 GCACGGAAATTTTTCT 103 1729 1156673 667 682 633 648CCGCCTGAGCCCCGGG 109 1730 1156706 798 813 764 779 CCAAGACAGCCACACG 901731 1156740 864 879 830 845 GACGGTTGAGAAGTGG 75 1732 1156774 927 942893 908 GATTAAAGTGTGATAG 84 1733 1156808 N/A N/A 981 996AACCCCCGGAACTTTT 99 1734 1156842 N/A N/A 1079 1094 TACTTAAATTACTAGC 721735 1156876 N/A N/A 1195 1210 CGCCTTTGTGAGGGAG 103 1736 1156910 10401055 1240 1255 TAGACGGAGAACAACT 71 1737 1156944 1132 1147 1332 1347GCGGTTTCCTCAAGCT 80 1738 1156978 1219 1234 1419 1434 CGCTAAGCAATATCTT 421739 1157011 1436 1451 1636 1651 TCTAAAAGCATTGCCC 71 1740 1157045 15541569 1754 1769 TCAAGGTCTTTTAATC 59 1741 1157078 1710 1725 1910 1925TCCCGTACTTCTGTCT 59 1742 1157112 2036 2051 2236 2251 TTGGTTACCAATAATT 761743 1157146 2209 2224 2409 2424 ATTACACCAGTCCTTT 60 1744 1157179 23232338 2523 2538 TTGAATTACTTCCGTT 46 1745 1157212 2409 2424 2609 2624CAATTAATGCTAGTCC 72 1746 1157246 2519 2534 2719 2734 CGCTTGCTCCTCAGTC 381747 1157280 2654 2669 2854 2869 CGCTCCTTCCTGGAAT 119 1748 1157313 27162731 2916 2931 CTCGCCTCCTCCGTGT 90 1749 1157347 2798 2813 2998 3013CGGATTTTTACCAACC 62 1750 1157381 2878 2893 3078 3093 GAAACTCCCCCATTAT 941751 1157447 3081 3096 3281 3296 GGCTATCAAATTCATT 58 1752 1157480 31983213 3398 3413 AAAACGAATTCAGGGT 75 1753 1157514 3312 3327 3512 3527TCTAGACAGACCTAAG 106 1754 1157547 3393 3408 3593 3608 TGTAAACCTGTGGTGG52 1755 1157579 3562 3577 3762 3777 TAAGACCATCCCAAAA 84 1756 11576133665 3680 3865 3880 CAGCGGTACACTCCTT 64 1757 1157646 3786 3801 3986 4001CTCCTGAGATGACTGA 61 1758 1157680 3915 3930 4115 4130 CCCAACCGTAACAGGC 781759 1157713 4037 4052 4237 4252 AGTTACTTGCCAACTT 93 1760 1157746 41254140 4325 4340 ATTAATGCACTGGTAC 84 1761 1157780 4243 4258 4443 4458GTTAATGTCAGCCCAG 45 1762 1157813 4383 4398 4583 4598 CTTCAGGATCATTAAG 971763 1157846 4594 4609 4793 4808 TGAACTATCACAATTC 76 1764 1157880 47124727 4911 4926 CATCATACTGCCAGGC 41 1765 1157912 4799 4814 4998 5013GCTTATTCCCCAATGG 27 1766 1157946 4888 4903 5087 5102 GTAACTTTAAATTGGT 451767 1157980 4980 4995 5179 5194 GATGGACATTGCCTCT 63 1768 1158013 51025117 5301 5316 CAATCCACTTGATCCC 44 1769 1158046 5165 5180 5364 5379TTCTGATAACGAAGAG 92 1770 1158079 5256 5271 5455 5470 ATCCCTAACATGCAAT 771771 1158111 5363 5378 5562 5577 GGCTCGATGGAAAAAT 67 1772 1158144 54265441 5625 5640 TCTGAGTGAAGTGTAC 66 1773 1158178 5552 5567 5751 5766CAGCACATCATGCTAT 85 1774 1158212 5740 5755 5939 5954 GAAGAATCCCCCCCAA 891775 1158244 5825 5840 6024 6039 CCTTAAAGTTACATTC 67 1776 1158277 59445959 6143 6158 TCATAATCTCCCACCT 90 1777 1158311 6051 6066 6250 6265GTTAACATGCAAACTT 87 1778 1158345 6113 6128 6312 6327 TCCCTATATAAGGTCA 951779 1158378 6256 6271 6455 6470 TCACTGCAAGGTCTCA 52 1780 1158411 64156430 6614 6629 ACTGCATTTACTTGCC 92 1781 1158444 6501 6516 6700 6715ACTACTCCAAGCATTG 64 1782 1158477 6594 6609 6793 6808 CAGCTTCAATCACAAA 671783 1158509 6838 6853 7037 7052 GTAAGAATTAAGACCA 63 1784 1158541 70157030 7214 7229 TTCAACTGGAAGCTCC 42 1785 1158574 7125 7140 7324 7339GCATAAAGCTGAAATC 96 1786 1158606 7252 7267 7451 7466 TTGTCCTACTTTAAGC 701787 1158640 7366 7381 7565 7580 GAGGGAGTTGAGGCAA 76 1788 1158673 74847499 7683 7698 AAGCACCGCTTGAGAT 92 1789 1158707‡ 7611 7626 7810 7825GCTAGATCAAAAGGCA 87 1790 1158741 7683 7698 7882 7897 AAACCGATTATGGATC 971791 1158775 7738 7753 7937 7952 GGCCTTTTCTAACATA 98 1792 1158807 78197834 8018 8033 AGTCACTGGATAAGTA 59 1793 1158840 7903 7918 8102 8117TCCAGTCTACAAGTTA 69 1794 1158873 8021 8036 8220 8235 CAGCTTCCGCTAAGAT111 1795 1158906 8182 8197 8381 8396 GAACCCCGTCCTGGAA 118 1796 11589388306 8321 8505 8520 ATATTGTGCTGTTACC 109 1797 1158972 8392 8407 85918606 TTATATTAGGTTCTCG 106 1798 1159005 8536 8551 N/A N/ATCCCCAATCAAGATTT 82 1799

TABLE 54 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: NO: NO: 1 NO: 1 2824 2824 Compound Start Stop StartStop MALAT1 SEQ ID Number Site Site Site Site Sequence (5′ to 3′)(% UTC) No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC 94 18 559497 3629 3644 3829 3844 AGTACTATAGCATCTG 114 32  559564 2839 28543039 3054 CCATAAGTAAGTTCCA 41 36  567919 6839 6854 7038 7053TGTAAGAATTAAGACC 82 1800  567964 7016 7031 7215 7230 ATTCAACTGGAAGCTC 831801  946411 4244 4259 4444 4459 AGTTAATGTCAGCCCA 66 1802  946418 65026517 6701 6716 CACTACTCCAAGCATT 77 1803  946423 7749 7764 7948 7963GGCAAATTAATGGCCT 75 1804 1156471 68 83 34 49 TGCGCTTAAGAGGGCA 93 18051156505 223 238 189 204 GGCCAGCCTATAAGGA 94 1806 1156538 330 345 296 311TCAGACCTTCTGAACC 106 1807 1156572 461 476 427 442 GTCTCCGAAGACACAG 1051808 1156606 516 531 482 497 ATGGAAAGCGAGTTCA 86 1809 1156640 585 600551 566 CGCACGGAAATTTTTC 117 1810 1156674 668 683 634 649CCCGCCTGAGCCCCGG 102 1811 1156707 807 822 773 788 GACTTGCTCCCAAGAC 931812 1156741 865 880 831 846 GGACGGTTGAGAAGTG 104 1813 1156775 928 943894 909 AGATTAAAGTGTGATA 73 1814 1156809 N/A N/A 982 997AAACCCCCGGAACTTT 95 1815 1156843 N/A N/A 1098 1113 CAAACTACACATGCAG 941816 1156877 N/A N/A 1196 1211 CCGCCTTTGTGAGGGA 86 1817 1156911 10411056 1241 1256 ATAGACGGAGAACAAC 79 1818 1156945 1133 1148 1333 1348TGCGGTTTCCTCAAGC 74 1819 1156979 1220 1235 1420 1435 ACGCTAAGCAATATCT 631820 1157012 1437 1452 1637 1652 ATCTAAAAGCATTGCC 82 1821 1157046 15621577 1762 1777 CATGGATTTCAAGGTC 89 1822 1157079 1712 1727 1912 1927CTTCCCGTACTTCTGT 57 1823 1157113 2037 2052 2237 2252 ATTGGTTACCAATAAT 961824 1157147 2210 2225 2410 2425 AATTACACCAGTCCTT 58 1825 1157180 23242339 2524 2539 CTTGAATTACTTCCGT 44 1826 1157213 2410 2425 2610 2625TCAATTAATGCTAGTC 65 1827 1157247 2521 2536 2721 2736 CTCGCTTGCTCCTCAG 461828 1157281 2657 2672 2857 2872 ACTCGCTCCTTCCTGG 52 1829 1157314 27172732 2917 2932 GCTCGCCTCCTCCGTG 73 1830 1157348 2799 2814 2999 3014ACGGATTTTTACCAAC 66 1831 1157382 2879 2894 3079 3094 CGAAACTCCCCCATTA 851832 1157415 2938 2953 3138 3153 AACCTACAACACCCGG 66 1833 1157448 30893104 3289 3304 CTCAATTTGGCTATCA 40 1834 1157481 3199 3214 3399 3414CAAAACGAATTCAGGG 74 1835 1157515 3313 3328 3513 3528 TTCTAGACAGACCTAA 711836 1157548 3394 3409 3594 3609 CTGTAAACCTGTGGTG 85 1837 1157580 35633578 3763 3778 TTAAGACCATCCCAAA 95 1838 1157614 3666 3681 3866 3881ACAGCGGTACACTCCT 58 1839 1157647 3794 3809 3994 4009 CTGAAGTTCTCCTGAG 621840 1157681 3916 3931 4116 4131 TCCCAACCGTAACAGG 98 1841 1157714 40394054 4239 4254 GGAGTTACTTGCCAAC 76 1842 1157747 4126 4141 4326 4341AATTAATGCACTGGTA 81 1843 1157814 4386 4401 4586 4601 TCCCTTCAGGATCATT 901844 1157847 4595 4610 4794 4809 CTGAACTATCACAATT 72 1845 1157881 47134728 4912 4927 CCATCATACTGCCAGG 83 1846 1157913 4800 4815 4999 5014TGCTTATTCCCCAATG 48 1847 1157947 4889 4904 5088 5103 CGTAACTTTAAATTGG 211848 1157981 4981 4996 5180 5195 AGATGGACATTGCCTC 52 1849 1158014 51035118 5302 5317 TCAATCCACTTGATCC 86 1850 1158047 5166 5181 5365 5380CTTCTGATAACGAAGA 105 1851 1158080 5258 5273 5457 5472 TTATCCCTAACATGCA92 1852 1158112 5364 5379 5563 5578 AGGCTCGATGGAAAAA 72 1853 11581455469 5484 5668 5683 CACTTTAGAGGCTTTT 58 1854 1158179 5555 5570 5754 5769TAACAGCACATCATGC 79 1855 1158213 5741 5756 5940 5955 AGAAGAATCCCCCCCA113 1856 1158245 5826 5841 6025 6040 GCCTTAAAGTTACATT 90 1857 11582785945 5960 6144 6159 ATCATAATCTCCCACC 80 1858 1158312 6068 6083 6267 6282GATTGTAAGCATTTAA 46 1859 1158346 6114 6129 6313 6328 TTCCCTATATAAGGTC 941860 1158379 6261 6276 6460 6475 TAAACTCACTGCAAGG 86 1861 1158412 64166431 6615 6630 TACTGCATTTACTTGC 80 1862 1158478 6601 6616 6800 6815ATGTACTCAGCTTCAA 56 1863 1158575 7129 7144 7328 7343 TCCAGCATAAAGCTGA109 1864 1158607 7258 7273 7457 7472 CCATGGTTGTCCTACT 90 1865 11586417367 7382 7566 7581 AGAGGGAGTTGAGGCA 60 1866 1158674 7486 7501 7685 7700TCAAGCACCGCTTGAG 112 1867 1158708‡ 7612 7627 7811 7826 TGCTAGATCAAAAGGC92 1868 1158742 7684 7699 7883 7898 GAAACCGATTATGGAT 66 1869 11588087823 7838 8022 8037 TTTTAGTCACTGGATA 55 1870 1158841 7912 7927 8111 8126CCTATCTTCTCCAGTC 113 1871 1158874 8023 8038 8222 8237 ATCAGCTTCCGCTAAG96 1872 1158907 8183 8198 8382 8397 TGAACCCCGTCCTGGA 97 1873 11589398307 8322 8506 8521 GATATTGTGCTGTTAC 117 1874 1158973 8393 8408 85928607 GTTATATTAGGTTCTC 93 1875 1159006 8538 8553 N/A N/A TTTCCCCAATCAAGAT104 1876

TABLE 55 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: NO: NO: 1 NO: 1 2824 2824 Compound Start Stop StartStop MALAT1 SEQ ID Number Site Site Site Site Sequence (5′ to 3′)(% UTC) No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC 78 18 559497 3629 3644 3829 3844 AGTACTATAGCATCTG 112 32  559564 2839 28543039 3054 CCATAAGTAAGTTCCA 36 36  946412 4715 4730 4914 4929GGCCATCATACTGCCA 119 1877  946425 8184 8199 8383 8398 TTGAACCCCGTCCTGG88 1878 1156472 69 84 35 50 CTGCGCTTAAGAGGGC 66 1879 1156506 228 243 194209 GGAATGGCCAGCCTAT 83 1880 1156539 331 346 297 312 TTCAGACCTTCTGAAC108 1881 1156573 469 484 435 450 ATGGCTTTGTCTCCGA 85 1882 1156607 517532 483 498 CATGGAAAGCGAGTTC 80 1883 1156641 586 601 552 567CCGCACGGAAATTTTT 85 1884 1156675 671 686 637 652 CTCCCCGCCTGAGCCC 1231885 1156708 808 823 774 789 CGACTTGCTCCCAAGA 78 1886 1156742 866 881832 847 GGGACGGTTGAGAAGT 93 1887 1156776 931 946 897 912GGAAGATTAAAGTGTG 79 1888 1156810 N/A N/A 983 998 AAAACCCCCGGAACTT 911889 1156844 N/A N/A 1106 1121 CTTGAATGCAAACTAC 106 1890 1156878 N/A N/A1197 1212 GCCGCCTTTGTGAGGG 75 1891 1156912 1042 1057 1242 1257TATAGACGGAGAACAA 70 1892 1156946 1134 1149 1334 1349 CTGCGGTTTCCTCAAG 711893 1156980 1232 1247 1432 1447 GTTAAAAACTTAACGC 96 1894 1157013 14381453 1638 1653 AATCTAAAAGCATTGC 70 1895 1157047 1563 1578 1763 1778TCATGGATTTCAAGGT 49 1896 1157080 1714 1729 1914 1929 GCCTTCCCGTACTTCT 401897 1157114 2040 2055 2240 2255 TAAATTGGTTACCAAT 75 1898 1157148 22112226 2411 2426 AAATTACACCAGTCCT 55 1899 1157181 2325 2340 2525 2540TCTTGAATTACTTCCG 24 1900 1157214 2411 2426 2611 2626 GTCAATTAATGCTAGT 591901 1157248 2522 2537 2722 2737 GCTCGCTTGCTCCTCA 61 1902 1157282 26592674 2859 2874 GCACTCGCTCCTTCCT 34 1903 1157315 2718 2733 2918 2933TGCTCGCCTCCTCCGT 66 1904 1157349 2800 2815 3000 3015 CACGGATTTTTACCAA 811905 1157383 2880 2895 3080 3095 ACGAAACTCCCCCATT 64 1906 1157416 29402955 3140 3155 GAAACCTACAACACCC 80 1907 1157449 3090 3105 3290 3305TCTCAATTTGGCTATC 71 1908 1157482 3200 3215 3400 3415 ACAAAACGAATTCAGG 691909 1157516 3314 3329 3514 3529 ATTCTAGACAGACCTA 67 1910 1157549 33953410 3595 3610 ACTGTAAACCTGTGGT 106 1911 1157581 3564 3579 3764 3779GTTAAGACCATCCCAA 81 1912 1157615 3667 3682 3867 3882 CACAGCGGTACACTCC 601913 1157648 3810 3825 4010 4025 GCCTACTCAAGCTCTT 80 1914 1157682 39173932 4117 4132 ATCCCAACCGTAACAG 87 1915 1157715 4040 4055 4240 4255GGGAGTTACTTGCCAA 90 1916 1157748 4128 4143 4328 4343 CAAATTAATGCACTGG 851917 1157781 4245 4260 4445 4460 TAGTTAATGTCAGCCC 59 1918 1157815 43874402 4587 4602 ATCCCTTCAGGATCAT 81 1919 1157848 4596 4611 4795 4810GCTGAACTATCACAAT 73 1920 1157914 4801 4816 5000 5015 ATGCTTATTCCCCAAT 481921 1157948 4890 4905 5089 5104 CCGTAACTTTAAATTG 45 1922 1157982 49824997 5181 5196 GAGATGGACATTGCCT 42 1923 1158015 5104 5119 5303 5318CTCAATCCACTTGATC 68 1924 1158048 5168 5183 5367 5382 CTCTTCTGATAACGAA 771925 1158081 5259 5274 5458 5473 CTTATCCCTAACATGC 59 1926 1158113 53655380 5564 5579 AAGGCTCGATGGAAAA 93 1927 1158146 5471 5486 5670 5685ATCACTTTAGAGGCTT 47 1928 1158180 5556 5571 5755 5770 CTAACAGCACATCATG 681929 1158214 5742 5757 5941 5956 GAGAAGAATCCCCCCC 83 1930 1158246 58275842 6026 6041 TGCCTTAAAGTTACAT 81 1931 1158279 5946 5961 6145 6160GATCATAATCTCCCAC 59 1932 1158313 6069 6084 6268 6283 AGATTGTAAGCATTTA 581933 1158347 6115 6130 6314 6329 CTTCCCTATATAAGGT 90 1934 1158380 62656280 6464 6479 CTGATAAACTCACTGC 52 1935 1158413 6419 6434 6618 6633CAGTACTGCATTTACT 80 1936 1158445 6503 6518 6702 6717 TCACTACTCCAAGCAT 791937 1158479 6602 6617 6801 6816 AATGTACTCAGCTTCA 52 1938 1158510 68426857 7041 7056 GCATGTAAGAATTAAG 72 1939 1158542 7018 7033 7217 7232GAATTCAACTGGAAGC 93 1940 1158576 7130 7145 7329 7344 CTCCAGCATAAAGCTG 881941 1158608 7259 7274 7458 7473 TCCATGGTTGTCCTAC 65 1942 1158642 73877402 7586 7601 TCGGATGCTTCACTCC 63 1943 1158675 7487 7502 7686 7701TTCAAGCACCGCTTGA 88 1944 1158709‡ 7613 7628 7812 7827 GTGCTAGATCAAAAGG75 1945 1158743 7685 7700 7884 7899 TGAAACCGATTATGGA 97 1946 11587767750 7765 7949 7964 AGGCAAATTAATGGCC 92 1947 1158809 7824 7839 8023 8038GTTTTAGTCACTGGAT 42 1948 1158842 7913 7928 8112 8127 GCCTATCTTCTCCAGT 731949 1158875 8027 8042 8226 8241 GGAGATCAGCTTCCGC 107 1950 1158940 83088323 8507 8522 AGATATTGTGCTGTTA 83 1951 1158974 8394 8409 8593 8608AGTTATATTAGGTTCT 78 1952 1159007 995 1010 N/A N/A CGCCTCTTAAAGCACT 1121953

TABLE 56 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: NO: NO: 1 NO: 1 2824 2824 Compound Start Stop StartStop MALAT1 SEQ ID Number Site Site Site Site Sequence (5′ to 3′)(% UTC) No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC 82 18 559497 3629 3644 3829 3844 AGTACTATAGCATCTG 126 32  559564 2839 28543039 3054 CCATAAGTAAGTTCCA 49 36  946399 230 245 196 211CTGGAATGGCCAGCCT 85 1954  946408 3668 3683 3868 3883 GCACAGCGGTACACTC 911955  946415 5743 5758 5942 5957 AGAGAAGAATCCCCCC 72 1956 1156473 71 8637 52 CGCTGCGCTTAAGAGG 90 1957 1156540 338 353 304 319 TATGAGCTTCAGACCT109 1958 1156574 473 488 439 454 GCGAATGGCTTTGTCT 93 1959 1156608 519534 485 500 GCCATGGAAAGCGAGT 91 1960 1156642 587 602 553 568CCCGCACGGAAATTTT 83 1961 1156676 672 687 638 653 GCTCCCCGCCTGAGCC 921962 1156709 810 825 776 791 TGCGACTTGCTCCCAA 113 1963 1156743 867 882833 848 AGGGACGGTTGAGAAG 86 1964 1156777 945 960 911 926TACCACCTTTTGAAGG 87 1965 1156811 N/A N/A 984 999 CAAAACCCCCGGAACT 1001966 1156845 N/A N/A 1107 1122 ACTTGAATGCAAACTA 89 1967 1156879 N/A N/A1199 1214 CCGCCGCCTTTGTGAG 75 1968 1156913 1043 1058 1243 1258TTATAGACGGAGAACA 92 1969 1156947 1135 1150 1335 1350 TCTGCGGTTTCCTCAA 511970 1156981 1233 1248 1433 1448 CGTTAAAAACTTAACG 87 1971 1157014 14581473 1658 1673 GTTTAAGTCACCTTCA 37 1972 1157048 1564 1579 1764 1779GTCATGGATTTCAAGG 48 1973 1157081 1715 1730 1915 1930 CGCCTTCCCGTACTTC 431974 1157115 2061 2076 2261 2276 TAAATTGATGGGCTTT 63 1975 1157149 22122227 2412 2427 TAAATTACACCAGTCC 56 1976 1157182 2327 2342 2527 2542GATCTTGAATTACTTC 51 1977 1157215 2412 2427 2612 2627 TGTCAATTAATGCTAG 581978 1157249 2524 2539 2724 2739 TTGCTCGCTTGCTCCT 60 1979 1157283 26602675 2860 2875 TGCACTCGCTCCTTCC 67 1980 1157316 2719 2734 2919 2934CTGCTCGCCTCCTCCG 84 1981 1157350 2801 2816 3001 3016 TCACGGATTTTTACCA 721982 1157384 2881 2896 3081 3096 TACGAAACTCCCCCAT 94 1983 1157417 29412956 3141 3156 AGAAACCTACAACACC 106 1984 1157450 3094 3109 3294 3309ATTGTCTCAATTTGGC 37 1985 1157483 3201 3216 3401 3416 TACAAAACGAATTCAG 801986 1157517 3316 3331 3516 3531 GGATTCTAGACAGACC 56 1987 1157550 33963411 3596 3611 AACTGTAAACCTGTGG 108 1988 1157582 3565 3580 3765 3780TGTTAAGACCATCCCA 91 1989 1157649 3811 3826 4011 4026 GGCCTACTCAAGCTCT 861990 1157683 3919 3934 4119 4134 CAATCCCAACCGTAAC 91 1991 1157716 40414056 4241 4256 TGGGAGTTACTTGCCA 81 1992 1157749 4129 4144 4329 4344CCAAATTAATGCACTG 87 1993 1157782 4246 4261 4446 4461 GTAGTTAATGTCAGCC 411994 1157816 4388 4403 4588 4603 AATCCCTTCAGGATCA 92 1995 1157849 45974612 4796 4811 AGCTGAACTATCACAA 95 1996 1157882 4717 4732 4916 4931TAGGCCATCATACTGC 94 1997 1157915 4803 4818 5002 5017 TTATGCTTATTCCCCA 251998 1157949 4891 4906 5090 5105 TCCGTAACTTTAAATT 64 1999 1157983 49834998 5182 5197 TGAGATGGACATTGCC 26 2000 1158016 5105 5120 5304 5319CCTCAATCCACTTGAT 102 2001 1158049 5171 5186 5370 5385 CAACTCTTCTGATAAC84 2002 1158082 5260 5275 5459 5474 ACTTATCCCTAACATG 87 2003 11581145367 5382 5566 5581 AAAAGGCTCGATGGAA 89 2004 1158147 5472 5487 5671 5686GATCACTTTAGAGGCT 108 2005 1158181 5557 5572 5756 5771 TCTAACAGCACATCAT78 2006 1158247 5829 5844 6028 6043 CCTGCCTTAAAGTTAC 80 2007 11582805947 5962 6146 6161 TGATCATAATCTCCCA 57 2008 1158314 6071 6086 6270 6285TAAGATTGTAAGCATT 77 2009 1158348 6116 6131 6315 6330 CCTTCCCTATATAAGG141 2010 1158381 6266 6281 6465 6480 GCTGATAAACTCACTG 45 2011 11584146421 6436 6620 6635 AACAGTACTGCATTTA 64 2012 1158446 6504 6519 6703 6718ATCACTACTCCAAGCA 80 2013 1158480 6606 6621 6805 6820 GCAAAATGTACTCAGC 772014 1158511 6846 6861 7045 7060 TCCTGCATGTAAGAAT 85 2015 1158543 70197034 7218 7233 TGAATTCAACTGGAAG 64 2016 1158577 7134 7149 7333 7348GTTACTCCAGCATAAA 100 2017 1158609 7260 7275 7459 7474 CTCCATGGTTGTCCTA61 2018 1158643 7388 7403 7587 7602 TTCGGATGCTTCACTC 52 2019 11586767488 7503 7687 7702 CTTCAAGCACCGCTTG 79 2020 1158710‡ 7615 7630 78147829 CTGTGCTAGATCAAAA 72 2021 1158744 7686 7701 7885 7900TTGAAACCGATTATGG 58 2022 1158777 7751 7766 7950 7965 CAGGCAAATTAATGGC 772023 1158810 7825 7840 8024 8039 GGTTTTAGTCACTGGA 15 2024 1158843 79207935 8119 8134 CTCAAATGCCTATCTT 81 2025 1158876 8028 8043 8227 8242TGGAGATCAGCTTCCG 82 2026 1158908 8185 8200 8384 8399 TTTGAACCCCGTCCTG 942027 1158941 8309 8324 8508 8523 AAGATATTGTGCTGTT 87 2028 1158975 83958410 8594 8609 CAGTTATATTAGGTTC 92 2029 1159008 996 1011 N/A N/ACCGCCTCTTAAAGCAC 109 2030

TABLE 57 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ NO: NO: NO: 1 ID NO: 2824 2824 Compound Start 1 Stop StartStop MALAT1 SEQ Number Site Site Site Site Sequence (5′ to 3′) (% UTC)ID No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC 105 18  5594973629 3644 3829 3844 AGTACTATAGCATCTG 123 32  559564 2839 2854 3039 3054CCATAAGTAAGTTCCA 51 36 1156475 113 128 79 94 GCTGAGGCTTCCCGGC 85 20311156508 235 250 201 216 ACCACCTGGAATGGCC 85 2032 1156542 341 356 307 322AGGTATGAGCTTCAGA 99 2033 1156576 475 490 441 456 AAGCGAATGGCTTTGT 942034 1156610 521 536 487 502 TCGCCATGGAAAGCGA 85 2035 1156644 590 605556 571 CGGCCCGCACGGAAAT 76 2036 1156678 680 695 646 661ACAGAGCTGCTCCCCG 82 2037 1156711 812 827 778 793 CCTGCGACTTGCTCCC 802038 1156745 870 885 836 851 TGCAGGGACGGTTGAG 122 2039 1156779 949 964915 930 AGTTTACCACCTTTTG 77 2040 1156813 N/A N/A 986 1001CACAAAACCCCCGGAA 81 2041 1156847 N/A N/A 1112 1127 ATGGAACTTGAATGCA 992042 1156881 N/A N/A 1205 1220 CACCTTCCGCCGCCTT 125 2043 1156915 10451060 1245 1260 ATTTATAGACGGAGAA 91 2044 1156949 1138 1153 1338 1353TTATCTGCGGTTTCCT 55 2045 1156983 1286 1301 1486 1501 CTACTCTTCTAAGTCT 512046 1157016 1460 1475 1660 1675 CTGTTTAAGTCACCTT 24 2047 1157050 15791594 1779 1794 CGCAATTCTCCCTGCG 77 2048 1157083 1718 1733 1918 1933CTTCGCCTTCCCGTAC 65 2049 1157117 2063 2078 2263 2278 ATTAAATTGATGGGCT 802050 1157151 2239 2254 2439 2454 CCAAAAGCCTTCTGCC 66 2051 1157184 23342349 2534 2549 TACTCTTGATCTTGAA 54 2052 1157217 2415 2430 2615 2630AGCTGTCAATTAATGC 90 2053 1157251 2536 2551 2736 2751 ACGAACTGCTGCTTGC 342054 1157285 2663 2678 2863 2878 AATTGCACTCGCTCCT 71 2055 1157318 27352750 2935 2950 CCTCTACGCACAACGC 41 2056 1157352 2803 2818 3003 3018CCTCACGGATTTTTAC 101 2057 1157386 2883 2898 3083 3098 AGTACGAAACTCCCCC72 2058 1157419 2960 2975 3160 3175 GAGTATAAGCCTGAAA 84 2059 11574523112 3127 3312 3327 GCTTACAGATTTGCTG 92 2060 1157485 3208 3223 3408 3423CTACATTTACAAAACG 71 2061 1157519 3318 3333 3518 3533 TAGGATTCTAGACAGA 442062 1157552 3417 3432 3617 3632 AGAACTGCTCTAGTTT 106 2063 1157584 35673582 3767 3782 CCTGTTAAGACCATCC 60 2064 1157617 3672 3687 3872 3887AACAGCACAGCGGTAC 98 2065 1157651 3813 3828 4013 4028 TTGGCCTACTCAAGCT108 2066 1157685 3922 3937 4122 4137 CACCAATCCCAACCGT 95 2067 11577184043 4058 4243 4258 ATTGGGAGTTACTTGC 37 2068 1157751 4132 4147 4332 4347TGCCCAAATTAATGCA 71 2069 1157784 4249 4264 4449 4464 ATTGTAGTTAATGTCA 502070 1157818 4398 4413 4598 4613 CATCAGAAGAAATCCC 83 2071 1157851 46024617 4801 4816 ATTCAAGCTGAACTAT 90 2072 1157884 4720 4735 4919 4934ATCTAGGCCATCATAC 68 2073 1157917 4806 4821 5005 5020 GGGTTATGCTTATTCC 722074 1157951 4895 4910 5094 5109 AGATTCCGTAACTTTA 22 2075 1157985 50165031 5215 5230 CGCTTTTATTCTGCTT 94 2076 1158018 5109 5124 5308 5323GCCTCCTCAATCCACT 84 2077 1158051 5213 5228 5412 5427 TTAACAGCTGCCTGCT 442078 1158084 5262 5277 5461 5476 GCACTTATCCCTAACA 42 2079 1158116 53695384 5568 5583 TAAAAAGGCTCGATGG 61 2080 1158149 5476 5491 5675 5690CACTGATCACTTTAGA 59 2081 1158183 5562 5577 5761 5776 CTGATTCTAACAGCAC 452082 1158216 5745 5760 5944 5959 TTAGAGAAGAATCCCC 69 2083 1158249 58705885 6069 6084 ATTATATGCTCATCAC 49 2084 1158282 5950 5965 6149 6164CTCTGATCATAATCTC 65 2085 1158316 6073 6088 6272 6287 TCTAAGATTGTAAGCA 472086 1158350 6168 6183 6367 6382 ATGAAATGCCTCTGCA 87 2087 1158383 62706285 6469 6484 GTATGCTGATAAACTC 48 2088 1158416 6426 6441 6625 6640ATCAGAACAGTACTGC 65 2089 1158448 6507 6522 6706 6721 ACAATCACTACTCCAA 692090 1158482 6669 6684 6868 6883 AAGGCTTCAGTCCCCT 86 2091 1158513 68536868 7052 7067 TGAGTGTTCCTGCATG 64 2092 1158545 7021 7036 7220 7235GGTGAATTCAACTGGA 51 2093 1158579 7136 7151 7335 7350 CAGTTACTCCAGCATA 762094 1158611 7267 7282 7466 7481 AGGAAGGCTCCATGGT 89 2095 1158645 73907405 7589 7604 CCTTCGGATGCTTCAC 42 2096 1158678 7491 7506 7690 7705CCCCTTCAAGCACCGC 86 2097 1158712‡ 7622 7637 7821 7836 GAAGGGTCTGTGCTAG60 2098 1158746 7688 7703 7887 7902 CCTTGAAACCGATTAT 64 2099 11587797753 7768 7952 7967 TGCAGGCAAATTAATG 89 2100 1158812 7835 7850 8034 8049GGTTTAAGTTGGTTTT 10 2101 1158845 7925 7940 8124 8139 AGCCACTCAAATGCCT 722102 1158878 8032 8047 8231 8246 GCATTGGAGATCAGCT 89 2103 1158910 81878202 8386 8401 GATTTGAACCCCGTCC 102 2104 1158943 8311 8326 8510 8525CAAAGATATTGTGCTG 110 2105 1158977 8397 8412 8596 8611 GGCAGTTATATTAGGT84 2106 1159010 998 1013 N/A N/A CGCCGCCTCTTAAAGC 87 2107

TABLE 58 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: 1 NO: 1 NO: 2824 NO: 2824 Compound Start Stop StartStop MALAT1 SEQ Number Site Site Site Site Sequence (5′ to 3′) (% UTC)ID No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC 113   18  5560333320 3335 3520 3535 TTTAGGATTCTAGACA  75 2108  559497 3629 3644 38293844 AGTACTATAGCATCTG 124   32  559564 2839 2854 3039 3054CCATAAGTAAGTTCCA  31   36  568503 7762 7777 7961 7976 TTAACAATTTGCAGGC 34 2109  946409 3936 3951 4136 4151 ACCTAAACCCACCCCA 101 2110 1156477 119  134   85  100 AGGCGAGCTGAGGCTT  81 2111 1156510  238  253  204 219 ACCACCACCTGGAATG  78 2112 1156544  343  358  309  324TTAGGTATGAGCTTCA  82 2113 1156578  477  492  443  458 CTAAGCGAATGGCTTT 78 2114 1156612  524  539  490  505 AAATCGCCATGGAAAG  99 2115 1156646 592  607  558  573 CACGGCCCGCACGGAA 101 2116 1156680  698  713  664 679 ACGCCTCAATCCCACA  73 2117 1156713  815  830  781  796AGTCCTGCGACTTGCT  74 2118 1156747  874  889  840  855 GCCTTGCAGGGACGGT110 2119 1156781  951  966  917  932 ATAGTTTACCACCTTT  61 2120 1156815N/A N/A  988 1003 CTCACAAAACCCCCGG  82 2121 1156849 N/A N/A 1114 1129TTATGGAACTTGAATG  93 2122 1156883 1008 1023 1208 1223 GATCACCTTCCGCCGC 94 2123 1156917 1048 1063 1248 1263 CGTATTTATAGACGGA 109 2124 11569511140 1155 1340 1355 ACTTATCTGCGGTTTC  29 2125 1156985 1289 1304 14891504 ATGCTACTCTTCTAAG  60 2126 1157018 1467 1482 1667 1682CTTTAAGCTGTTTAAG 104 2127 1157052 1582 1597 1782 1797 TGACGCAATTCTCCCT 67 2128 1157085 1726 1741 1926 1941 ATTCTTTTCTTCGCCT  52 2129 11571192077 2092 2277 2292 CTGCACCACCAGAAAT  80 2130 1157153 2271 2286 24712486 TATTTAAGGCCTTCCA  38 2131 1157186 2336 2351 2536 2551ATTACTCTTGATCTTG  29 2132 1157219 2423 2438 2623 2638 CCTGGGTCAGCTGTCA 49 2133 1157253 2538 2553 2738 2753 CCACGAACTGCTGCTT  46 2134 11572872665 2680 2865 2880 CAAATTGCACTCGCTC  66 2135 1157320 2737 2752 29372952 ATCCTCTACGCACAAC  58 2136 1157354 2807 2822 3007 3022CCGACCTCACGGATTT  61 2137 1157388 2885 2900 3085 3100 TCAGTACGAAACTCCC 59 2138 1157421 2962 2977 3162 3177 ATGAGTATAAGCCTGA  45 2139 11574543115 3130 3315 3330 ACTGCTTACAGATTTG  39 2140 1157487 3223 3238 34233438 TTACACATCCAAACTC  99 2141 1157554 3419 3434 3619 3634TGAGAACTGCTCTAGT  65 2142 1157586 3569 3584 3769 3784 TCCCTGTTAAGACCAT 73 2143 1157619 3675 3690 3875 3890 GCCAACAGCACAGCGG  92 2144 11576533817 3832 4017 4032 ACATTTGGCCTACTCA  54 2145 1157720 4045 4060 42454260 TCATTGGGAGTTACTT  43 2146 1157753 4143 4158 4343 4358GACACTTTCCTTGCCC  52 2147 1157786 4254 4269 4454 4469 CCATAATTGTAGTTAA 93 2148 1157820 4404 4419 4604 4619 AGCTACCATCAGAAGA  66 2149 11578534604 4619 4803 4818 ACATTCAAGCTGAACT 105 2150 1157886 4724 4739 49234938 CTGCATCTAGGCCATC  35 2151 1157919 4808 4823 5007 5022CAGGGTTATGCTTATT  25 2152 1157953 4897 4912 5096 5111 GTAGATTCCGTAACTT 27 2153 1157987 5018 5033 5217 5232 TTCGCTTTTATTCTGC  31 2154 11580205128 5143 5327 5342 AACATTGGCACACAGC  46 2155 1158053 5215 5230 54145429 TGTTAACAGCTGCCTG  61 2156 1158086 5264 5279 5463 5478AAGCACTTATCCCTAA  75 2157 1158118 5371 5386 5570 5585 TTTAAAAAGGCTCGAT 72 2158 1158151 5481 5496 5680 5695 CAAGGCACTGATCACT  52 2159 11581855567 5582 5766 5781 AACATCTGATTCTAAC  73 2160 1158218 5767 5782 59665981 CGCAGACAAAGTTTCT  43 2161 1158251 5880 5895 6079 6094GCCTGGAATTATTATA  69 2162 1158284 5952 5967 6151 6166 TACTCTGATCATAATC 83 2163 1158318 6075 6090 6274 6289 ACTCTAAGATTGTAAG  75 2164 11583526171 6186 6370 6385 AGGATGAAATGCCTCT  78 2165 1158385 6273 6288 64726487 TGAGTATGCTGATAAA  59 2166 1158418 6431 6446 6630 6645GCGGGATCAGAACAGT  60 2167 1158450 6509 6524 6708 6723 CAACAATCACTACTCC 84 2168 1158484 6673 6688 6872 6887 ACTAAAGGCTTCAGTC  74 2169 11585156878 6893 7077 7092 TGGCCCTTCGCATACG  72 2170 1158547 7026 7041 72257240 CCACTGGTGAATTCAA  45 2171 1158581 7142 7157 7341 7356ACATGCCAGTTACTCC  61 2172 1158613 7273 7288 7472 7487 TGCCACAGGAAGGCTC110 2173 1158647 7392 7407 7591 7606 TTCCTTCGGATGCTTC  50 2174 11586807493 7508 7692 7707 CTCCCCTTCAAGCACC  96 2175 1158714 7642 7657 78417856 GCTGCATCGAGGTGAG  76 2176 1158748 7690 7705 7889 7904TACCTTGAAACCGATT  64 2177 1158814 7839 7854 8038 8053 TACTGGTTTAAGTTGG 33 2178 1158847 7938 7953 8137 8152 CAAAAGCCCTCTCAGC 114 2179 11588808034 8049 8233 8248 GAGCATTGGAGATCAG  71 2180 1158912 8189 8204 83888403 GGGATTTGAACCCCGT 101 2181 1158945 8322 8337 8521 8536TGTATATAGTTCAAAG  91 2182 1158979 8402 8417 8601 8616 GACAAGGCAGTTATAT 99 2183 1159012 1001 1016 N/A N/A TTCCGCCGCCTCTTAA  78 2184

TABLE 59 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: 1 NO: 1 NO: 2824 NO: 2824 Compound Start Stop StartStop MALAT1 SEQ Number Site Site Site Site Sequence (5′ to 3′) (% UTC)ID No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC  92   18  5594973629 3644 3829 3844 AGTACTATAGCATCTG 112   32  559564 2839 2854 30393054 CCATAAGTAAGTTCCA  37   36 1156476  114  129   80   95AGCTGAGGCTTCCCGG  88 2185 1156509  236  251  202  217 CACCACCTGGAATGGC 92 2186 1156543  342  357  308  323 TAGGTATGAGCTTCAG  96 2187 1156577 476  491  442  457 TAAGCGAATGGCTTTG  93 2188 1156611  523  538  489 504 AATCGCCATGGAAAGC 104 2189 1156645  591  606  557  572ACGGCCCGCACGGAAA  84 2190 1156679  696  711  662  677 GCCTCAATCCCACACC 98 2191 1156712  813  828  779  794 TCCTGCGACTTGCTCC  85 2192 1156746 871  886  837  852 TTGCAGGGACGGTTGA 110 2193 1156780  950  965  916 931 TAGTTTACCACCTTTT  85 2194 1156814 N/A N/A  987 1002TCACAAAACCCCCGGA  84 2195 1156848 N/A N/A 1113 1128 TATGGAACTTGAATGC  762196 1156882 1007 1022 1207 1222 ATCACCTTCCGCCGCC  85 2197 1156916 10471062 1247 1262 GTATTTATAGACGGAG 100 2198 1156950 1139 1154 1339 1354CTTATCTGCGGTTTCC  38 2199 1156984 1288 1303 1488 1503 TGCTACTCTTCTAAGT 81 2200 1157017 1462 1477 1662 1677 AGCTGTTTAAGTCACC  38 2201 11570511581 1596 1781 1796 GACGCAATTCTCCCTG  73 2202 1157084 1720 1735 19201935 TTCTTCGCCTTCCCGT  34 2203 1157118 2064 2079 2264 2279AATTAAATTGATGGGC  83 2204 1157152 2270 2285 2470 2485 ATTTAAGGCCTTCCAA 70 2205 1157185 2335 2350 2535 2550 TTACTCTTGATCTTGA  34 2206 11572182422 2437 2622 2637 CTGGGTCAGCTGTCAA  67 2207 1157252 2537 2552 27372752 CACGAACTGCTGCTTG  45 2208 1157286 2664 2679 2864 2879AAATTGCACTCGCTCC  72 2209 1157319 2736 2751 2936 2951 TCCTCTACGCACAACG 89 2210 1157353 2806 2821 3006 3021 CGACCTCACGGATTTT  84 2211 11573872884 2899 3084 3099 CAGTACGAAACTCCCC  70 2212 1157420 2961 2976 31613176 TGAGTATAAGCCTGAA  75 2213 1157453 3114 3129 3314 3329CTGCTTACAGATTTGC  51 2214 1157486 3218 3233 3418 3433 CATCCAAACTCTACAT 77 2215 1157520 3319 3334 3519 3534 TTAGGATTCTAGACAG  57 2216 11575533418 3433 3618 3633 GAGAACTGCTCTAGTT  66 2217 1157585 3568 3583 37683783 CCCTGTTAAGACCATC  79 2218 1157618 3673 3688 3873 3888CAACAGCACAGCGGTA 105 2219 1157652 3816 3831 4016 4031 CATTTGGCCTACTCAA 66 2220 1157686 3923 3938 4123 4138 CCACCAATCCCAACCG  74 2221 11577194044 4059 4244 4259 CATTGGGAGTTACTTG  68 2222 1157752 4141 4156 43414356 CACTTTCCTTGCCCAA  31 2223 1157785 4250 4265 4450 4465AATTGTAGTTAATGTC  64 2224 1157819 4403 4418 4603 4618 GCTACCATCAGAAGAA 78 2225 1157852 4603 4618 4802 4817 CATTCAAGCTGAACTA  61 2226 11578854722 4737 4921 4936 GCATCTAGGCCATCAT  43 2227 1157918 4807 4822 50065021 AGGGTTATGCTTATTC  37 2228 1157952 4896 4911 5095 5110TAGATTCCGTAACTTT  42 2229 1157986 5017 5032 5216 5231 TCGCTTTTATTCTGCT 78 2230 1158019 5126 5141 5325 5340 CATTGGCACACAGCAC  79 2231 11580525214 5229 5413 5428 GTTAACAGCTGCCTGC  93 2232 1158085 5263 5278 54625477 AGCACTTATCCCTAAC  60 2233 1158117 5370 5385 5569 5584TTAAAAAGGCTCGATG  79 2234 1158150 5477 5492 5676 5691 GCACTGATCACTTTAG 37 2235 1158184 5564 5579 5763 5778 ATCTGATTCTAACAGC  60 2236 11582175747 5762 5946 5961 GATTAGAGAAGAATCC  86 2237 1158250 5876 5891 60756090 GGAATTATTATATGCT  46 2238 1158283 5951 5966 6150 6165ACTCTGATCATAATCT  65 2239 1158317 6074 6089 6273 6288 CTCTAAGATTGTAAGC 84 2240 1158351 6170 6185 6369 6384 GGATGAAATGCCTCTG  76 2241 11583846272 6287 6471 6486 GAGTATGCTGATAAAC  63 2242 1158417 6430 6445 66296644 CGGGATCAGAACAGTA  76 2243 1158449 6508 6523 6707 6722AACAATCACTACTCCA  74 2244 1158483 6672 6687 6871 6886 CTAAAGGCTTCAGTCC 77 2245 1158514 6855 6870 7054 7069 GCTGAGTGTTCCTGCA  78 2246 11585467022 7037 7221 7236 TGGTGAATTCAACTGG  67 2247 1158580 7141 7156 73407355 CATGCCAGTTACTCCA  67 2248 1158612 7269 7284 7468 7483ACAGGAAGGCTCCATG  75 2249 1158646 7391 7406 7590 7605 TCCTTCGGATGCTTCA 44 2250 1158679 7492 7507 7691 7706 TCCCCTTCAAGCACCG  81 2251 11587137640 7655 7839 7854 TGCATCGAGGTGAGGG  79 2252 1158747 7689 7704 78887903 ACCTTGAAACCGATTA  55 2253 1158780 7761 7776 7960 7975TAACAATTTGCAGGCA  40 2254 1158813 7837 7852 8036 8051 CTGGTTTAAGTTGGTT 39 2255 1158846 7935 7950 8134 8149 AAGCCCTCTCAGCCAC  62 2256 11588798033 8048 8232 8247 AGCATTGGAGATCAGC  64 2257 1158911 8188 8203 83878402 GGATTTGAACCCCGTC  70 2258 1158944 8314 8329 8513 8528GTTCAAAGATATTGTG 100 2259 1158978 8398 8413 8597 8612 AGGCAGTTATATTAGG 74 2260 1159011 1000 1015 N/A N/A TCCGCCGCCTCTTAAA  74 2261

TABLE 60 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: 1 NO: 1 NO: 2824 NO: 2824 Compound Start Stop StartStop MALAT1 SEQ Number Site Site Site Site Sequence (5′ to 3′) (% UTC)ID No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC  83   18  5594973629 3644 3829 3844 AGTACTATAGCATCTG  99   32  559564 2839 2854 30393054 CCATAAGTAAGTTCCA  27   36 1156474   99  114   65   80GCGCCGGGCTTCTGCG  71 2262 1156507  232  247  198  213 ACCTGGAATGGCCAGC 79 2263 1156541  339  354  305  320 GTATGAGCTTCAGACC 106 2264 1156575 474  489  440  455 AGCGAATGGCTTTGTC  95 2265 1156609  520  535  486 501 CGCCATGGAAAGCGAG  80 2266 1156643  588  603  554  569GCCCGCACGGAAATTT  77 2267 1156677  673  688  639  654 TGCTCCCCGCCTGAGC 76 2268 1156710  811  826  777  792 CTGCGACTTGCTCCCA  90 2269 1156744 869  884  835  850 GCAGGGACGGTTGAGA  92 2270 1156778  948  963  914 929 GTTTACCACCTTTTGA  97 2271 1156812 N/A N/A  985 1000ACAAAACCCCCGGAAC 253 2272 1156846 N/A N/A 1111 1126 TGGAACTTGAATGCAA  902273 1156880 N/A N/A 1203 1218 CCTTCCGCCGCCTTTG  79 2274 1156914 10441059 1244 1259 TTTATAGACGGAGAAC 106 2275 1156948 1136 1151 1336 1351ATCTGCGGTTTCCTCA  42 2276 1156982 1247 1262 1447 1462 AGCTATTAAAATTACG 78 2277 1157015 1459 1474 1659 1674 TGTTTAAGTCACCTTC  26 2278 11570491565 1580 1765 1780 CGTCATGGATTTCAAG  60 2279 1157082 1717 1732 19171932 TTCGCCTTCCCGTACT  37 2280 1157116 2062 2077 2262 2277TTAAATTGATGGGCTT  78 2281 1157150 2213 2228 2413 2428 TTAAATTACACCAGTC 50 2282 1157183 2333 2348 2533 2548 ACTCTTGATCTTGAAT  57 2283 11572162414 2429 2614 2629 GCTGTCAATTAATGCT  76 2284 1157250 2535 2550 27352750 CGAACTGCTGCTTGCT  60 2285 1157284 2661 2676 2861 2876TTGCACTCGCTCCTTC  67 2286 1157317 2721 2736 2921 2936 GCCTGCTCGCCTCCTC 59 2287 1157351 2802 2817 3002 3017 CTCACGGATTTTTACC  93 2288 11573852882 2897 3082 3097 GTACGAAACTCCCCCA  62 2289 1157418 2942 2957 31423157 GAGAAACCTACAACAC  89 2290 1157451 3100 3115 3300 3315GCTGAAATTGTCTCAA  55 2291 1157484 3202 3217 3402 3417 TTACAAAACGAATTCA 90 2292 1157518 3317 3332 3517 3532 AGGATTCTAGACAGAC  28 2293 11575513411 3426 3611 3626 GCTCTAGTTTCTATAA  73 2294 1157583 3566 3581 37663781 CTGTTAAGACCATCCC  54 2295 1157616 3670 3685 3870 3885CAGCACAGCGGTACAC  93 2296 1157650 3812 3827 4012 4027 TGGCCTACTCAAGCTC108 2297 1157684 3921 3936 4121 4136 ACCAATCCCAACCGTA  82 2298 11577174042 4057 4242 4257 TTGGGAGTTACTTGCC  30 2299 1157750 4130 4145 43304345 CCCAAATTAATGCACT  49 2300 1157783 4247 4262 4447 4462TGTAGTTAATGTCAGC  33 2301 1157817 4390 4405 4590 4605 GAAATCCCTTCAGGAT 86 2302 1157850 4599 4614 4798 4813 CAAGCTGAACTATCAC  73 2303 11578834719 4734 4918 4933 TCTAGGCCATCATACT  60 2304 1157916 4805 4820 50045019 GGTTATGCTTATTCCC  63 2305 1157950 4894 4909 5093 5108GATTCCGTAACTTTAA  31 2306 1157984 4984 4999 5183 5198 TTGAGATGGACATTGC 13 2307 1158017 5106 5121 5305 5320 TCCTCAATCCACTTGA  56 2308 11580505173 5188 5372 5387 AGCAACTCTTCTGATA  70 2309 1158083 5261 5276 54605475 CACTTATCCCTAACAT  90 2310 1158115 5368 5383 5567 5582AAAAAGGCTCGATGGA  48 2311 1158148 5475 5490 5674 5689 ACTGATCACTTTAGAG 64 2312 1158182 5560 5575 5759 5774 GATTCTAACAGCACAT  69 2313 11582155744 5759 5943 5958 TAGAGAAGAATCCCCC  66 2314 1158248 5863 5878 60626077 GCTCATCACTTTATGA  90 2315 1158281 5949 5964 6148 6163TCTGATCATAATCTCC  61 2316 1158315 6072 6087 6271 6286 CTAAGATTGTAAGCAT 72 2317 1158349 6117 6132 6316 6331 CCCTTCCCTATATAAG  95 2318 11583826267 6282 6466 6481 TGCTGATAAACTCACT  54 2319 1158415 6422 6437 66216636 GAACAGTACTGCATTT  72 2320 1158447 6505 6520 6704 6719AATCACTACTCCAAGC  71 2321 1158481 6609 6624 6808 6823 CCAGCAAAATGTACTC 54 2322 1158512 6851 6866 7050 7065 AGTGTTCCTGCATGTA  69 2323 11585447020 7035 7219 7234 GTGAATTCAACTGGAA  50 2324 1158578 7135 7150 73347349 AGTTACTCCAGCATAA  69 2325 1158610 7264 7279 7463 7478AAGGCTCCATGGTTGT  68 2326 1158644 7389 7404 7588 7603 CTTCGGATGCTTCACT 67 2327 1158677 7490 7505 7689 7704 CCCTTCAAGCACCGCT  72 2328 115871117616 7631 7815 7830 TCTGTGCTAGATCAAA  39 2329 1158745 7687 7702 78867901 CTTGAAACCGATTATG  62 2330 1158778 7752 7767 7951 7966GCAGGCAAATTAATGG  55 2331 1158811 7831 7846 8030 8045 TAAGTTGGTTTTAGTC 22 2332 1158844 7924 7939 8123 8138 GCCACTCAAATGCCTA  82 2333 11588778030 8045 8229 8244 ATTGGAGATCAGCTTC  48 2334 1158909 8186 8201 83858400 ATTTGAACCCCGTCCT  69 2335 1158942 8310 8325 8509 8524AAAGATATTGTGCTGT  89 2336 1158976 8396 8411 8595 8610 GCAGTTATATTAGGTT 85 2337 1159009 997 1012 N/A N/A GCCGCCTCTTAAAGCA 111 2338

TABLE 61 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: 1 NO: 1 NO: 2824 NO: 2824 Compound Start Stop StartStop MALAT1 SEQ Number Site Site Site Site Sequence (5′ to 3′) (% UTC)ID No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC  82   18  5560946674 6689 6873 6888 GACTAAAGGCTTCAGT  85 2339  559497 3629 3644 38293844 AGTACTATAGCATCTG 108   32  559564 2839 2854 3039 3054CCATAAGTAAGTTCCA  39   36  568456 3118 3133 3318 3333 CAAACTGCTTACAGAT 69 2340 1156478  120  135   86  101 CAGGCGAGCTGAGGCT  93 2341 1156511 243  258  209  224 TAAATACCACCACCTG  98 2342 1156545  344  359  310 325 GTTAGGTATGAGCTTC  85 2343 1156579  478  493  444  459ACTAAGCGAATGGCTT 109 2344 1156613  525  540  491  506 CAAATCGCCATGGAAA 86 2345 1156647  593  608  559  574 CCACGGCCCGCACGGA  94 2346 1156681 711  726  677  692 CCACTCTTGGAAAACG  77 2347 1156714  818  833  784 799 TGCAGTCCTGCGACTT  85 2348 1156748  875  890  841  856AGCCTTGCAGGGACGG 121 2349 1156782  952  967  918  933 TATAGTTTACCACCTT 86 2350 1156816 N/A N/A  989 1004 CCTCACAAAACCCCCG 113 2351 1156850 N/AN/A 1115 1130 CTTATGGAACTTGAAT 105 2352 1156884 1011 1026 1211 1226TTCGATCACCTTCCGC  88 2353 1156918 1062 1077 1262 1277 CAGCTCGGGCGAGGCG 87 2354 1156952 1141 1156 1341 1356 AACTTATCTGCGGTTT  94 2355 11569861293 1308 1493 1508 CCTCATGCTACTCTTC  46 2356 1157019 1492 1507 16921707 AATCACCTACAACTTT  74 2357 1157053 1583 1598 1783 1798ATGACGCAATTCTCCC  85 2358 1157086 1727 1742 1927 1942 TATTCTTTTCTTCGCC 51 2359 1157120 2080 2095 2280 2295 CTTCTGCACCACCAGA  87 2360 11571542273 2288 2473 2488 TATATTTAAGGCCTTC  55 2361 1157187 2337 2352 25372552 AATTACTCTTGATCTT  49 2362 1157220 2424 2439 2624 2639ACCTGGGTCAGCTGTC  86 2363 1157254 2539 2554 2739 2754 ACCACGAACTGCTGCT 48 2364 1157288 2666 2681 2866 2881 CCAAATTGCACTCGCT  64 2365 11573212739 2754 2939 2954 GGATCCTCTACGCACA  81 2366 1157355 2808 2823 30083023 GCCGACCTCACGGATT  55 2367 1157389 2886 2901 3086 3101CTCAGTACGAAACTCC  70 2368 1157422 2963 2978 3163 3178 CATGAGTATAAGCCTG 50 2369 1157488 3226 3241 3426 3441 CAGTTACACATCCAAA  55 2370 11575213321 3336 3521 3536 CTTTAGGATTCTAGAC  93 2371 1157555 3420 3435 36203635 GTGAGAACTGCTCTAG  64 2372 1157587 3624 3639 3824 3839TATAGCATCTGTGGAA  80 2373 1157620 3676 3691 3876 3891 TGCCAACAGCACAGCG 99 2374 1157654 3818 3833 4018 4033 AACATTTGGCCTACTC  58 2375 11576873937 3952 4137 4152 TACCTAAACCCACCCC  94 2376 1157721 4046 4061 42464261 ATCATTGGGAGTTACT  46 2377 1157754 4144 4159 4344 4359TGACACTTTCCTTGCC  34 2378 1157787 4255 4270 4455 4470 CCCATAATTGTAGTTA 55 2379 1157821 4410 4425 4610 4625 TACAAAAGCTACCATC  88 2380 11578544605 4620 4804 4819 GACATTCAAGCTGAAC  47 2381 1157887 4726 4741 49254940 CTCTGCATCTAGGCCA  60 2382 1157920 4809 4824 5008 5023TCAGGGTTATGCTTAT  36 2383 1157954 4898 4913 5097 5112 GGTAGATTCCGTAACT 40 2384 1157988 5045 5060 5244 5259 TAATGTAGTGTAACAT  71 2385 11580215132 5147 5331 5346 ACGAAACATTGGCACA  38 2386 1158054 5216 5231 54155430 CTGTTAACAGCTGCCT  48 2387 1158087 5266 5281 5465 5480ATAAGCACTTATCCCT  50 2388 1158119 5372 5387 5571 5586 TTTTAAAAAGGCTCGA 88 2389 1158152 5482 5497 5681 5696 TCAAGGCACTGATCAC  51 2390 11581865571 5586 5770 5785 CAGTAACATCTGATTC  43 2391 1158219 5768 5783 59675982 TCGCAGACAAAGTTTC  69 2392 1158252 5882 5897 6081 6096GTGCCTGGAATTATTA  61 2393 1158285 5957 5972 6156 6171 CCTTTTACTCTGATCA 44 2394 1158319 6076 6091 6275 6290 CACTCTAAGATTGTAA  67 2395 11583536173 6188 6372 6387 GAAGGATGAAATGCCT  93 2396 1158386 6274 6289 64736488 TTGAGTATGCTGATAA  39 2397 1158419 6432 6447 6631 6646AGCGGGATCAGAACAG  57 2398 1158451 6510 6525 6709 6724 TCAACAATCACTACTC 84 2399 1158516 6898 6913 7097 7112 CTTACTGGGTCTGGCT  59 2400 11585487033 7048 7232 7247 ATTTTGTCCACTGGTG  50 2401 1158582 7145 7160 73447359 CTCACATGCCAGTTAC  49 2402 1158614 7289 7304 7488 7503GCTTTGTTGTCTCTCC   7 2403 1158648 7394 7409 7593 7608 CATTCCTTCGGATGCT 62 2404 1158681 7512 7527 7711 7726 GCCCGCTTTCCCCCTT 129 2405 11587157648 7663 7847 7862 CTACTGGCTGCATCGA  46 2406 1158749 7691 7706 78907905 TTACCTTGAAACCGAT  69 2407 1158781 7763 7778 7962 7977GTTAACAATTTGCAGG  60 2408 1158815 7840 7855 8039 8054 TTACTGGTTTAAGTTG 76 2409 1158848 7940 7955 8139 8154 CCCAAAAGCCCTCTCA  88 2410 11588818035 8050 8234 8249 AGAGCATTGGAGATCA  80 2411 1158913 8190 8205 83898404 AGGGATTTGAACCCCG 103 2412 1158946 8324 8339 8523 8538GATGTATATAGTTCAA  93 2413 1158980 8419 8434 8618 8633 GGCTATTACCTGAAAA 94 2414 1159013 1002 1017 N/A N/A CTTCCGCCGCCTCTTA  91 2415

TABLE 62 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: 1 NO: 1 NO: 2824 NO: 2824 Compound Start Stop StartStop MALAT1 SEQ Number Site Site Site Site Sequence (5′ to 3′) (% UTC)ID No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC  87   18  5594973629 3644 3829 3844 AGTACTATAGCATCTG 123   32  559564 2839 2854 30393054 CCATAAGTAAGTTCCA  45   36  946419 6899 6914 7098 7113TCTTACTGGGTCTGGC  55 2416 1156479  121  136   87  102 TCAGGCGAGCTGAGGC 93 2417 1156512  244  259  210  225 CTAAATACCACCACCT  88 2418 1156546 345  360  311  326 GGTTAGGTATGAGCTT  92 2419 1156580  480  495  446 461 CAACTAAGCGAATGGC  76 2420 1156614  526  541  492  507GCAAATCGCCATGGAA  79 2421 1156648  594  609  560  575 CCCACGGCCCGCACGG 86 2422 1156682  717  732  683  698 GAAAACCCACTCTTGG  90 2423 1156715 825  840  791  806 AACTGCTTGCAGTCCT  95 2424 1156749  889  904  855 870 CGCAACTGAGCCCCAG  82 2425 1156783  953  968  919  934GTATAGTTTACCACCT  91 2426 1156817 N/A N/A  999 1014 TCATCAAACACCTCAC 1082427 1156851 N/A N/A 1116 1131 GCTTATGGAACTTGAA  90 2428 1156885 10121027 1212 1227 ATTCGATCACCTTCCG  81 2429 1156919 1064 1079 1264 1279CACAGCTCGGGCGAGG  75 2430 1156953 1142 1157 1342 1357 AAACTTATCTGCGGTT 81 2431 1156987 1327 1342 1527 1542 CCGTCATGTTTTAGAA  42 2432 11570201510 1525 1710 1725 TCGCCTTCAAATTATT  65 2433 1157054 1584 1599 17841799 AATGACGCAATTCTCC  79 2434 1157087 1728 1743 1928 1943CTATTCTTTTCTTCGC  63 2435 1157121 2084 2099 2284 2299 CTAACTTCTGCACCAC 62 2436 1157155 2274 2289 2474 2489 CTATATTTAAGGCCTT  74 2437 11571882338 2353 2538 2553 TAATTACTCTTGATCT  52 2438 1157221 2425 2440 26252640 CACCTGGGTCAGCTGT  75 2439 1157255 2540 2555 2740 2755CACCACGAACTGCTGC  81 2440 1157289 2667 2682 2867 2882 ACCAAATTGCACTCGC 60 2441 1157322 2741 2756 2941 2956 TAGGATCCTCTACGCA  77 2442 11573562809 2824 3009 3024 TGCCGACCTCACGGAT  76 2443 1157390 2887 2902 30873102 CCTCAGTACGAAACTC  84 2444 1157423 2966 2981 3166 3181ATTCATGAGTATAAGC  71 2445 1157455 3119 3134 3319 3334 ACAAACTGCTTACAGA 83 2446 1157489 3228 3243 3428 3443 CTCAGTTACACATCCA  30 2447 11575223323 3338 3523 3538 GCCTTTAGGATTCTAG  70 2448 1157556 3421 3436 36213636 CGTGAGAACTGCTCTA  63 2449 1157588 3625 3640 3825 3840CTATAGCATCTGTGGA  71 2450 1157621 3692 3707 3892 3907 TCCCTGAAGGTGTTCG 82 2451 1157655 3819 3834 4019 4034 CAACATTTGGCCTACT  83 2452 11576883938 3953 4138 4153 TTACCTAAACCCACCC  62 2453 1157722 4047 4062 42474262 AATCATTGGGAGTTAC  76 2454 1157755 4146 4161 4346 4361TATGACACTTTCCTTG  75 2455 1157788 4256 4271 4456 4471 TCCCATAATTGTAGTT 73 2456 1157822 4422 4437 4622 4637 CTTACTTGATAATACA  65 2457 11578554610 4625 4809 4824 TAAGAGACATTCAAGC  83 2458 1157888 4744 4759 49434958 TCACCAAGGAGCTGTT  88 2459 1157921 4810 4825 5009 5024CTCAGGGTTATGCTTA  60 2460 1157955 4900 4915 5099 5114 ATGGTAGATTCCGTAA 86 2461 1157989 5046 5061 5245 5260 TTAATGTAGTGTAACA  70 2462 11580225133 5148 5332 5347 AACGAAACATTGGCAC  52 2463 1158055 5217 5232 54165431 TCTGTTAACAGCTGCC  49 2464 1158088 5267 5282 5466 5481AATAAGCACTTATCCC  69 2465 1158120 5373 5388 5572 5587 ATTTTAAAAAGGCTCG 73 2466 1158153 5483 5498 5682 5697 ATCAAGGCACTGATCA  77 2467 11581875572 5587 5771 5786 GCAGTAACATCTGATT  43 2468 1158220 5769 5784 59685983 TTCGCAGACAAAGTTT  78 2469 1158253 5885 5900 6084 6099CATGTGCCTGGAATTA  74 2470 1158286 5958 5973 6157 6172 ACCTTTTACTCTGATC 66 2471 1158320 6077 6092 6276 6291 CCACTCTAAGATTGTA  60 2472 11583546174 6189 6373 6388 TGAAGGATGAAATGCC  71 2473 1158387 6275 6290 64746489 TTTGAGTATGCTGATA  53 2474 1158420 6433 6448 6632 6647CAGCGGGATCAGAACA  77 2475 1158452 6512 6527 6711 6726 CTTCAACAATCACTAC 98 2476 1158485 6675 6690 6874 6889 AGACTAAAGGCTTCAG  88 2477 11585497055 7070 7254 7269 AGCTTGTTCACCTGTT  63 2478 1158583 7146 7161 73457360 GCTCACATGCCAGTTA  68 2479 1158615 7290 7305 7489 7504CGCTTTGTTGTCTCTC  13 2480 1158649 7396 7411 7595 7610 AGCATTCCTTCGGATG 86 2481 1158682 7514 7529 7713 7728 TTGCCCGCTTTCCCCC  81 2482 11587167649 7664 7848 7863 GCTACTGGCTGCATCG  57 2483 1158750 7692 7707 78917906 GTTACCTTGAAACCGA  53 2484 1158782 7764 7779 7963 7978TGTTAACAATTTGCAG  80 2485 1158816 7842 7857 8041 8056 ACTTACTGGTTTAAGT103 2486 1158849 7941 7956 8140 8155 ACCCAAAAGCCCTCTC  87 2487 11588828036 8051 8235 8250 AAGAGCATTGGAGATC  67 2488 1158914 8193 8208 83928407 CGCAGGGATTTGAACC  85 2489 1158947 8325 8340 8524 8539GGATGTATATAGTTCA  70 2490 1158981 8420 8435 8619 8634 AGGCTATTACCTGAAA105 2491 1159014 1003 1018 N/A N/A CCTTCCGCCGCCTCTT  97 2492

TABLE 63 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: 1 NO: 1 NO: 2824 NO: 2824 Compound Start Stop StartStop MALAT1 SEQ Number Site Site Site Site Sequence (5′ to 3′) (% UTC)ID No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC  80   18  5594973629 3644 3829 3844 AGTACTATAGCATCTG 112   32  559564 2839 2854 30393054 CCATAAGTAAGTTCCA  40   36  568447 2339 2354 2539 2554GTAATTACTCTTGATC  53 2493 1156480  123  138   89  104 CTTCAGGCGAGCTGAG104 2494 1156513  248  263  214  229 TTATCTAAATACCACC  98 2495 1156547 346  361  312  327 TGGTTAGGTATGAGCT  96 2496 1156581  481  496  447 462 CCAACTAAGCGAATGG  82 2497 1156615  527  542  493  508GGCAAATCGCCATGGA  78 2498 1156649  595  610  561  576 CCCCACGGCCCGCACG109 2499 1156683  718  733  684  699 TGAAAACCCACTCTTG 100 2500 1156716 827  842  793  808 CCAACTGCTTGCAGTC  75 2501 1156750  890  905  856 871 ACGCAACTGAGCCCCA 144 2502 1156784  955  970  921  936AGGTATAGTTTACCAC 107 2503 1156818 N/A N/A 1004 1019 ACGGGTCATCAAACAC  862504 1156852 N/A N/A 1117 1132 AGCTTATGGAACTTGA  84 2505 1156886 10131028 1213 1228 AATTCGATCACCTTCC  84 2506 1156920 1065 1080 1265 1280GCACAGCTCGGGCGAG 120 2507 1156954 1143 1158 1343 1358 AAAACTTATCTGCGGT 46 2508 1156988 1328 1343 1528 1543 TCCGTCATGTTTTAGA  50 2509 11570211511 1526 1711 1726 ATCGCCTTCAAATTAT  40 2510 1157055 1586 1601 17861801 TAAATGACGCAATTCT  92 2511 1157088 1805 1820 2005 2020GCTTCCTACTTTTCAG  56 2512 1157122 2086 2101 2286 2301 TTCTAACTTCTGCACC 67 2513 1157156 2275 2290 2475 2490 ACTATATTTAAGGCCT  60 2514 11572222427 2442 2627 2642 AGCACCTGGGTCAGCT 105 2515 1157256 2543 2558 27432758 CTTCACCACGAACTGC  57 2516 1157290 2668 2683 2868 2883CACCAAATTGCACTCG  46 2517 1157323 2742 2757 2942 2957 CTAGGATCCTCTACGC 89 2518 1157357 2810 2825 3010 3025 TTGCCGACCTCACGGA N.D. 2519 11573912891 2906 3091 3106 TACACCTCAGTACGAA  72 2520 1157424 2967 2982 31673182 GATTCATGAGTATAAG  50 2521 1157456 3120 3135 3320 3335TACAAACTGCTTACAG  61 2522 1157490 3229 3244 3429 3444 CCTCAGTTACACATCC 51 2523 1157523 3324 3339 3524 3539 TGCCTTTAGGATTCTA  55 2524 11575573436 3451 3636 3651 TTCCACAGACCTCAAC 104 2525 1157589 3626 3641 38263841 ACTATAGCATCTGTGG  91 2526 1157622 3693 3708 3893 3908GTCCCTGAAGGTGTTC  77 2527 1157656 3820 3835 4020 4035 TCAACATTTGGCCTAC 79 2528 1157689 3939 3954 4139 4154 ATTACCTAAACCCACC 110 2529 11577234048 4063 4248 4263 AAATCATTGGGAGTTA  76 2530 1157756 4156 4171 43564371 AGTATCAAATTATGAC N.D. 2531 1157789 4257 4272 4457 4472TTCCCATAATTGTAGT  82 2532 1157823 4423 4438 4623 4638 TCTTACTTGATAATAC 90 2533 1157856 4611 4626 4810 4825 CTAAGAGACATTCAAG  73 2534 11578894745 4760 4944 4959 TTCACCAAGGAGCTGT  63 2535 1157922 4811 4826 50105025 TCTCAGGGTTATGCTT  41 2536 1157956 4901 4916 5100 5115AATGGTAGATTCCGTA  53 2537 1157990 5048 5063 5247 5262 GATTAATGTAGTGTAA 77 2538 1158023 5134 5149 5333 5348 AAACGAAACATTGGCA  54 2539 11580565218 5233 5417 5432 ATCTGTTAACAGCTGC  29 2540 1158089 5268 5283 54675482 AAATAAGCACTTATCC  82 2541 1158121 5385 5400 5584 5599ACAAGTCCTACAATTT  69 2542 1158154 5484 5499 5683 5698 CATCAAGGCACTGATC 87 2543 1158188 5573 5588 5772 5787 AGCAGTAACATCTGAT  59 2544 11582215770 5785 5969 5984 GTTCGCAGACAAAGTT  64 2545 1158254 5893 5908 60926107 TCTATTGCCATGTGCC  59 2546 1158287 5959 5974 6158 6173TACCTTTTACTCTGAT  58 2547 1158321 6078 6093 6277 6292 ACCACTCTAAGATTGT111 2548 1158355 6190 6205 6389 6404 ATCCTGAATGGCTTCA 100 2549 11583886278 6293 6477 6492 AATTTTGAGTATGCTG  46 2550 1158421 6434 6449 66336648 GCAGCGGGATCAGAAC  66 2551 1158453 6534 6549 6733 6748TATCACTCAGCTGGAT  66 2552 1158486 6676 6691 6875 6890 AAGACTAAAGGCTTCA 79 2553 1158517 6920 6935 7119 7134 TAAAGTAAATAGGCTA  79 2554 11585507058 7073 7257 7272 AAAAGCTTGTTCACCT  79 2555 1158584 7148 7163 73477362 TTGCTCACATGCCAGT  60 2556 1158616 7304 7319 7503 7518CCTTAGGATAATAGCG  40 2557 1158650 7397 7412 7596 7611 AAGCATTCCTTCGGAT108 2558 1158683 7520 7535 7719 7734 AAGTGGTTGCCCGCTT  78 2559 11587177650 7665 7849 7864 AGCTACTGGCTGCATC N.D. 2560 1158751 7693 7708 78927907 CGTTACCTTGAAACCG  64 2561 1158783 7773 7788 7972 7987ATACCCTTCTGTTAAC  98 2562 1158817 7844 7859 8043 8058 CCACTTACTGGTTTAA 67 2563 1158850 7942 7957 8141 8156 CACCCAAAAGCCCTCT  83 2564 11588838037 8052 8236 8251 GAAGAGCATTGGAGAT  51 2565 1158915 8194 8209 83938408 CCGCAGGGATTTGAAC  98 2566 1158948 8326 8341 8525 8540AGGATGTATATAGTTC  98 2567 1158982 8421 8436 8620 8635 CAGGCTATTACCTGAA114 2568 1159015 1004 1019 N/A N/A ACCTTCCGCCGCCTCT  67 2569

TABLE 64 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: 1 NO: 1 NO: 2824 NO: 2824 Compound Start Stop StartStop MALAT1 SEQ Number Site Site Site Site Sequence (5′ to 3′) (% UTC)ID No.  395254 4843 4862 5042 5061 GGCATATGCAGATAATGTTC  97   18  5594973629 3644 3829 3844 AGTACTATAGCATCTG 141   32  559564 2839 2854 30393054 CCATAAGTAAGTTCCA  52   36  567926 4746 4761 4945 4960ATTCACCAAGGAGCTG  61 2570  568506 8195 8210 8394 8409 GCCGCAGGGATTTGAA 69 2571 1156481  130  145   96  111 GACCTGCCTTCAGGCG N.D. 2572 1156514 251  266  217  232 GTTTTATCTAAATACC  71 2573 1156548  347  362  313 328 CTGGTTAGGTATGAGC  97 2574 1156582  482  497  448  463ACCAACTAAGCGAATG 112 2575 1156616  528  543  494  509 AGGCAAATCGCCATGG 95 2576 1156650  597  612  563  578 CCCCCCACGGCCCGCA  74 2577 1156684 719  734  685  700 GTGAAAACCCACTCTT  90 2578 1156717  828  843  794 809 CCCAACTGCTTGCAGT  91 2579 1156751  891  906  857  872TACGCAACTGAGCCCC 100 2580 1156785  956  971  922  937 TAGGTATAGTTTACCA 98 2581 1156819 N/A N/A 1005 1020 AACGGGTCATCAAACA 125 2582 1156853 N/AN/A 1118 1133 CAGCTTATGGAACTTG 133 2583 1156887 1014 1029 1214 1229GAATTCGATCACCTTC 101 2584 1156921 1067 1082 1267 1282 CCGCACAGCTCGGGCG 86 2585 1156955 1144 1159 1344 1359 AAAAACTTATCTGCGG  51 2586 11569891329 1344 1529 1544 CTCCGTCATGTTTTAG  33 2587 1157022 1512 1527 17121727 GATCGCCTTCAAATTA  61 2588 1157056 1587 1602 1787 1802TTAAATGACGCAATTC  96 2589 1157089 1831 1846 2031 2046 GTTTCCTAGCTTGTCT 43 2590 1157123 2089 2104 2289 2304 ACCTTCTAACTTCTGC  36 2591 11571572276 2291 2476 2491 TACTATATTTAAGGCC  99 2592 1157189 2340 2355 25402555 GGTAATTACTCTTGAT  50 2593 1157223 2431 2446 2631 2646GTGTAGCACCTGGGTC  36 2594 1157257 2545 2560 2745 2760 ATCTTCACCACGAACT 78 2595 1157291 2669 2684 2869 2884 TCACCAAATTGCACTC  79 2596 11573242743 2758 2943 2958 TCTAGGATCCTCTACG 124 2597 1157358 2813 2828 30133028 ATATTGCCGACCTCAC  74 2598 1157392 2892 2907 3092 3107TTACACCTCAGTACGA  85 2599 1157425 2970 2985 3170 3185 CAAGATTCATGAGTAT 66 2600 1157457 3121 3136 3321 3336 ATACAAACTGCTTACA 130 2601 11574913233 3248 3433 3448 CCCGCCTCAGTTACAC  96 2602 1157524 3332 3347 35323547 GAGTCATTTGCCTTTA  27 2603 1157558 3445 3460 3645 3660GGACATCTCTTCCACA  76 2604 1157590 3627 3642 3827 3842 TACTATAGCATCTGTG107 2605 1157623 3694 3709 3894 3909 AGTCCCTGAAGGTGTT  72 2606 11576573822 3837 4022 4037 CTTCAACATTTGGCCT  82 2607 1157690 3940 3955 41404155 AATTACCTAAACCCAC 100 2608 1157724 4049 4064 4249 4264TAAATCATTGGGAGTT  62 2609 1157757 4183 4198 4383 4398 CTCTATACTTTGAAGG 80 2610 1157790 4261 4276 4461 4476 GCATTTCCCATAATTG  54 2611 11578244426 4441 4626 4641 GAATCTTACTTGATAA  87 2612 1157857 4613 4628 48124827 CTCTAAGAGACATTCA  77 2613 1157923 4814 4829 5013 5028GAATCTCAGGGTTATG  43 2614 1157957 4902 4917 5101 5116 AAATGGTAGATTCCGT 40 2615 1157991 5049 5064 5248 5263 GGATTAATGTAGTGTA  14 2616 11580245135 5150 5334 5349 CAAACGAAACATTGGC  69 2617 1158057 5219 5234 54185433 TATCTGTTAACAGCTG  59 2618 1158090 5285 5300 5484 5499AACTCCACAGCTCTTA N.D. 2619 1158122 5387 5402 5586 5601 GAACAAGTCCTACAAT 68 2620 1158155 5485 5500 5684 5699 GCATCAAGGCACTGAT  65 2621 11581895574 5589 5773 5788 TAGCAGTAACATCTGA  54 2622 1158222 5772 5787 59715986 GTGTTCGCAGACAAAG  90 2623 1158255 5894 5909 6093 6108CTCTATTGCCATGTGC  43 2624 1158288 5991 6006 6190 6205 ACCCCTGACTTTCTGG 82 2625 1158322 6079 6094 6278 6293 TACCACTCTAAGATTG  95 2626 11583566194 6209 6393 6408 CAAAATCCTGAATGGC  90 2627 1158389 6323 6338 65226537 GTAAGCCCCACCCCCT 135 2628 1158422 6435 6450 6634 6649AGCAGCGGGATCAGAA  81 2629 1158454 6536 6551 6735 6750 TTTATCACTCAGCTGG 47 2630 1158487 6694 6709 6893 6908 TTAAGGTTGCATCTGG  35 2631 11585186966 6981 7165 7180 TAGTGGTTCCCAATCC  86 2632 1158551 7060 7075 72597274 GAAAAAGCTTGTTCAC  72 2633 1158585 7151 7166 7350 7365AGTTTGCTCACATGCC  35 2634 1158617 7305 7320 7504 7519 ACCTTAGGATAATAGC 61 2635 1158651 7398 7413 7597 7612 CAAGCATTCCTTCGGA  75 2636 11586847521 7536 7720 7735 AAAGTGGTTGCCCGCT  85 2637 1158718 7653 7668 78527867 CCAAGCTACTGGCTGC  77 2638 1158752 7707 7722 7906 7921GACCTCGACACCATCG  56 2639 1158784 7774 7789 7973 7988 AATACCCTTCTGTTAA 84 2640 1158818 7870 7885 8069 8084 TTACAGTTCTTGAACA  75 2641 11588517947 7962 8146 8161 ATTCCCACCCAAAAGC N.D. 2642 1158884 8039 8054 82388253 CTGAAGAGCATTGGAG  50 2643 1158949 8327 8342 8526 8541AAGGATGTATATAGTT  79 2644 1158983 8422 8437 8621 8636 GCAGGCTATTACCTGA 81 2645 1159016 1005 1020 N/A N/A CACCTTCCGCCGCCTC  72 2646

Example 14: Design of Gapmers with 2′-O Methyl ModificationsComplementary to Human MALAT1 RNA

Modified oligonucleotides complementary to human a MALAT1 nucleic acidwere designed. The modified oligonucleotides in the table below are3-10-3 cET gapmers. The gapmers are 16 nucleosides in length, whereinthe central gap segment comprises of a combination of one 2′-O-methylnucleoside and nine 2′-deoxynucleosides. The central gap segment isflanked by wing segments on the 5′ direction and the 3′ directioncomprising three nucleosides each. Each nucleoside in the 5′ wingsegment and each nucleoside in the 3′ wing segment has a cEt sugarmodification. The internucleoside linkages throughout each gapmer arephosphorothioate (P═S) linkages. The sequence and chemical notationcolumn specifies the sequence, including 5-methylcytosines, sugarchemistry, and the internucleoside linkage chemistry; wherein subscript‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, subscript ‘k’represents a cET sugar moiety, subscript ‘s’ represents to aphosphorothioate internucleoside linkage, superscript ‘m’ before thecytosine residue represents a 5-methylcytosine, and subscript ‘y’represents a 2′-OMe sugar moiety. “Start site” indicates the 5′-mostnucleoside to which the gapmer is complementary in the human nucleicacid sequence. “Stop site” indicates the 3′-most nucleoside to which thegapmer is complementary in the human nucleic acid sequence.

Each modified oligonucleotide listed in the table below is complementaryto human MALAT1 nucleic acid sequence SEQ ID NO: 1 (GENBANK AccessionNo: XR_001309.1).

TABLE 65 cET gapmers with 2′-OMe sugars complementary to human MALAT1SEQ SEQ ID ID NO: 1 NO: 1 SEQ Compound Start Stop ID Number Site SiteSequence (5′ to 3′) Chemistry Notation (5′ to 3′) No. 1304879 2033 2048GTTACCAATAATTTCC G_(ks)T_(ks)T_(ks)A_(ds)C_(ys)^(m)C_(ds)A_(ds)A_(ds)T_(ds)A_(ds)A_(ds)T_(ds)T_(ds)T_(ks) ^(m)C_(ks)^(m)C_(k) 1592 1304880 5078 5093 TCTCATTTATTTCGGC T_(ks)^(m)C_(ks)T_(ks)^(m)C_(ds)A_(ys)T_(ds)T_(ds)T_(ds)A_(ds)T_(ds)T_(ds)T_(ds)^(m)C_(ds)G_(ks)G_(ks) ^(m)C_(k) 1077 1304881 5494 5509 CCTTAGTTGGCATCAA^(m)C_(ks) ^(m)C_(ks)T_(ks)T_(ds)A_(ys)G_(ds)T_(ds)T_(ds)G_(ds)G_(ds)^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ks)A_(ks)A_(k)    6 1304882 5419 5434GAAGUGTACTATCCCA G_(ks)A_(ks)A_(ks)G_(ds)U_(ys)G_(ds)T_(ds)A_(ds)^(m)C_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(k) 26471304883 5074 5089 ATTTATTTCGGCTTCTA_(ks)T_(ks)T_(ks)T_(ds)A_(ys)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)G_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ks) ^(m)C_(ks)T_(k)  850 1304885 4938 4953TTTTUGTGGTTATAGCT_(ks)T_(ks)T_(ks)T_(ds)U_(ys)G_(ds)T_(ds)G_(ds)G_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ks)G_(ks)^(m)C_(k) 2648 1304886 4903 4918 AAAAUGGTAGATTCCGA_(ks)A_(ks)A_(ks)A_(ds)U_(ys)G_(ds)G_(ds)T_(ds)A_(ds)G_(ds)A_(ds)T_(ds)T_(ds)^(m)C_(ks) ^(m)C_(ks)G_(k) 2649 1304887 4935 4950 TTGTGGTTATAGCTTGT_(ks)T_(ks)G_(ks)T_(ds)G_(ys)G_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)G_(ds)^(m)C_(ds)T_(ks)T_(ks)G_(k) 1232 1304888 4933 4948 GTGGUTATAGCTTGACG_(ks)T_(ks)G_(ks)G_(ds)U_(ys)T_(ds)A_(ds)T_(ds)A_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)G_(ks)A_(ks) ^(m)C_(k) 2650 1304889 4808 4823CAGGGTTATGCTTATT^(m)C_(ks)A_(ks)G_(ks)G_(ds)G_(ys)T_(ds)T_(ds)A_(ds)T_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ks)T_(ks)T_(k) 2152 1304891 2034 2049GGTTACCAATAATTTC G_(ks)G_(ks)T_(ks)T_(ds)A_(ys) ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(ds)T_(ds)A_(ds)A_(ds)T_(ds)T_(ks)T_(ks) ^(m)C_(k)   3 1304892 2341 2356 TGGTAATTACTCTTGAT_(ks)G_(ks)G_(ks)T_(ds)A_(ys)A_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ks)G_(ks)A_(k)    4 1304893 1533 1548CGGTUTAATCTCTTTT^(m)C_(ks)G_(ks)G_(ks)T_(ds)U_(ys)T_(ds)A_(ds)A_(ds)T_(ds)^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ks)T_(ks)T_(k) 2651 1304894 72907305 CGCTUTGTTGTCTCTC ^(m)C_(ks)G_(ks)^(m)C_(ks)T_(ds)U_(ys)T_(ds)G_(ds)T_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds)T_(ds) ^(m)C_(ks)T_(ks) ^(m)C_(k) 2652 1304895 7835 7850GGTTUAAGTTGGTTTTG_(ks)G_(ks)T_(ks)T_(ds)U_(ys)A_(ds)A_(ds)G_(ds)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds)T_(ks)T_(ks)T_(k)2653 1304896 7825 7840 GGTTUTAGTCACTGGAG_(ks)G_(ks)T_(ks)T_(ds)U_(ys)T_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ks)G_(ks)A_(k) 2654 1304897 7289 7304GCTTUGTTGTCTCTCC G_(ks)^(m)C_(ks)T_(ks)T_(ds)U_(ys)G_(ds)T_(ds)T_(ds)G_(ds)T_(ds)^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(k) 2655 1304898 54955510 TCCTUAGTTGGCATCA T_(ks) ^(m)C_(ks)^(m)C_(ks)T_(ds)U_(ys)A_(ds)G_(ds)T_(ds)T_(ds)G_(ds)G_(ds)^(m)C_(ds)A_(ds)T_(ks) ^(m)C_(ks)A_(k) 2656 1304899 6700 6715CTGAUTTTAAGGTTGC^(m)C_(ks)T_(ks)G_(ks)A_(ds)U_(ys)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ks)G_(ks)^(m)C_(k) 2657 1304900 6699 6714 TGATUTTAAGGTTGCAT_(ks)G_(ks)A_(ks)T_(ds)U_(ys)T_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds)G_(ks)^(m)C_(ks)A_(k) 2658 1304901 5525 5540 AGCCUTCAGAGATTCA A_(ks)G_(ks)^(m)C_(ks) ^(m)C_(ds)U_(ys)T_(ds)^(m)C_(ds)A_(ds)G_(ds)A_(ds)G_(ds)A_(ds)T_(ds)T_(ks) ^(m)C_(ks)A_(k)2659 1304902 5050 5065 AGGAUTAATGTAGTGTA_(ks)G_(ks)G_(ks)A_(ds)U_(ys)T_(ds)A_(ds)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)G_(ds)T_(ks)G_(ks)T_(k)2660 1304903 5051 5066 CAGGATTAATGTAGTG^(m)C_(ks)A_(ks)G_(ks)G_(ds)A_(ys)T_(ds)T_(ds)A_(ds)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)G_(ks)T_(ks)G_(k) 161 1304904 4821 4836 GTAGUAAGAATCTCAGG_(ks)T_(ks)A_(ks)G_(ds)U_(ys)A_(ds)A_(ds)G_(ds)A_(ds)A_(ds)T_(ds)^(m)C_(ds)T_(ds) ^(m)C_(ks)A_(ks)G_(k) 2661 1304905 1564 1579GTCAUGGATTTCAAGG G_(ks)T_(ks)^(m)C_(ks)A_(ds)U_(ys)G_(ds)G_(ds)A_(ds)T_(ds)T_(ds)T_(ds)^(m)C_(ds)sA_(ds)A_(ks)G_(ks)G_(k) 2662 1304907 1535 1550TTCGGTTTAATCTCTT T_(ks)T_(ks)^(m)C_(ks)G_(ds)G_(ys)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)T_(ds)^(m)C_(ds)T_(ds) ^(m)C_(ks)T_(ks)T_(k)    2 1304908 4932 4947TGGTUATAGCTTGACA T_(ks)G_(ks)G_(ks)T_(ds)U_(ys)A_(ds)T_(ds)A_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ks) ^(m)C_(ks)A_(k) 2663

Example 15: Antisense Inhibition of Human MALAT1 in HepG2 Cells by3-10-3 cEt Gapmers

Modified oligonucleotides complementary to a MALAT1 nucleic acid weresynthesized and tested for their effect on MALAT1 RNA levels in vitro incomparison with comparator compounds 395240 and 556089 described above.The modified oligonucleotides were tested in a series of experimentsusing the same culture conditions. The results for each separateexperiment are presented in separate tables below.

Except for comparator compound 395240, which is a 5-10-5 MOE gapmer(i.e., it has a central gap segment of ten 2′-deoxynucleosides flankedon each side by wing segments, each comprising five 2′-O-methoxyethylmodified nucleosides), the modified oligonucleotides are all 3-10-3 cEtgapmers (i.e., they have a central gap segment of ten2′-deoxynucleosides flanked on each side by wing segments, eachcomprising three cEt modified nucleosides). The internucleoside linkagesthroughout each modified oligonucleotide are phosphorothioate (P═S)linkages. All cytosine nucleobases throughout each modifiedoligonucleotide are 5-methylcytosines.

“Start site” indicates the 5′-most nucleoside of the target sequence towhich the modified oligonucleotide is complementary. “Stop site”indicates the 3′-most nucleoside of the target sequence to which themodified oligonucleotide is complementary. As shown in the tables below,the modified oligonucleotides are 100% complementary to either the humanMALAT1 RNA transcript, designated herein as SEQ ID NO: 1 (GENBANKAccession No. XR_001309.1) or the human MALAT1 RNA transcript designatedhere in as SEQ ID NO: 2824 (GENBANK Accession No. EF177381.1). ‘N/A’indicates that the modified oligonucleotide is not complementary to thatparticular target sequence with 100% complementarity.

Cultured HepG2 cells at a density of 20,000 cells per well weretransfected using electroporation with 300 nM of modifiedoligonucleotide. After an overnight incubation, RNA was isolated fromthe cells and MALAT1 RNA levels were measured by quantitative real-timeRTPCR. Human primer probe set RTS2738 (forward sequenceGAATTGCGTCATTTAAAGCCTAGTT, designated herein as SEQ ID NO: 2820; reversesequence TCATCCTACCACTCCCAATTAATCT, designated herein as SEQ ID NO:2821; probe sequence ACGCATTTACTAAACGCAGACGAAAATGGA, designated hereinas SEQ ID NO: 2822) was used to measure RNA levels. MALAT1 RNA levelswere normalized to total RNA content, as measured by RIBOGREEN®. Resultsare presented as percent change of MALAT1 RNA, relative to PBS control.The symbol “‡” indicates that the modified oligonucleotide iscomplementary to the target transcript within the amplicon region of theprimer probe set and so the associated data is not reliable. In suchinstances, additional assays using alternative primer probes must beperformed to accurately assess the potency and efficacy of such modifiedoligonucleotides.

TABLE 66 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: 1 NO: 1 NO: 2824 NO: 2824 Compound Start Stop StartStop MALAT1 SEQ Number Site Site Site Site Sequence (5′ to 3′) (% UTC)ID No. 395240 3320 3339 3520 3539 TGCCTTTAGGATTCTAGACA  51   11 5560323310 3325 3510 3525 TAGACAGACCTAAGGG  22 2664 556089 6445 6460 6644 6659GCATTCTAATAGCAGC   6   31 556130 8007 8022 8206 8221 ATGCTAGCTTGGCCAA 17 2665 559466   36   51    2   17 GGGCCCCAGTCCTTTA  86 2666 559467 177  192  143  158 CGTCCCAAGGACTCTG 105 2667 559468  281  296  247  262ACCCCAAGACCAAACT  93 2668 559469  412  427  378  393 AAGTGTTTACACTGCT 74 2669 559470  522  537  488  503 ATCGCCATGGAAAGCG  95 2670 559471 636  651  602  617 GTGGCCCACTCTGATC  87 2671 559472  760  775  726  741TCGGAGCAGCACGGGC  77 2672 559473  868  883  834  849 CAGGGACGGTTGAGAA 91 2673 559474  968  983  934  949 CTTGAGGGACAGTAGG  84 2674 559475 N/AN/A 1051 1066 TTGAGCTGCAAACTTT 119 2675 559476 N/A N/A 1162 1177GGTTAAAAATAGGTTC  73 2676 559477 1063 1078 1263 1278 ACAGCTCGGGCGAGGC 74 2677 559478 1199 1214 1399 1414 ACCTATTGACTATATT  33 2678 5594791415 1430 1615 1630 TTGGTATTAATTCGGG   8 2679 559480 1561 1576 1761 1776ATGGATTTCAAGGTCT   7 2680 559481 1690 1705 1890 1905 GTTTTCCACTTCAAAC 35 2681 559482 1953 1968 2153 2168 CAATACTTGTCTTAGC  13 2682 5594842178 2193 2378 2393 GTGATTTTTAACCAAC   7 2683 559485 2399 2414 2599 2614TAGTCCTCAGGATTTA  21 2684 559486 2503 2518 2703 2718 CTAGCTTCATCAAACA 22 2685 559487 2626 2641 2826 2841 CTTCACCACCAAATCG  20 2686 5594882752 2767 2952 2967 GCATGCTGGTCTAGGA  22 2687 559489 2789 2804 2989 3004ACCAACCACTCGCTTT  22 2688 559490 2889 2904 3089 3104 CACCTCAGTACGAAAC 42 2689 559491 2985 3000 3185 3200 CTCAAAAGCTTCAGAC  29 2690 5594922997 3012 3197 3212 TGGCAGTCTGCCCTCA  22 2691 559493 3166 3181 3366 3381GTCATCTATTCACAAA   8 2692 559494 3322 3337 3522 3537 CCTTTAGGATTCTAGA 17 2693 559495 3435 3450 3635 3650 TCCACAGACCTCAACG  17 2694 5594963502 3517 3702 3717 AAAGTCTGATTAAGGG  18 2695 559497 3629 3644 3829 3844AGTACTATAGCATCTG   8   32 559498 3720 3735 3920 3935 ACTCTTCCAAGGATAA 17 2696 559499 3766 3781 3966 3981 GAACCAAAGCTGCACT  17 2697 5595003884 3899 4084 4099 GCCAATATTTGCCCCT  22 2698 559501 4022 4037 4222 4237TGGAAGTTGATATTTC  10 2699 559502 4080 4095 4280 4295 GCTTCCCAATTCAAAC 37 2700 559503 4182 4197 4382 4397 TCTATACTTTGAAGGA  33 2701 5595044295 4310 4495 4510 GAGAACCACACACTAC  23 2702 559505 4405 4420 4605 4620AAGCTACCATCAGAAG  29 2703 559506 4575 4590 4774 4789 ATCAGTTACAATTTAC 12 2704 559507 4629 4644 4828 4843 TCAACAAAAGCCCACC  48 2705 5595084687 4702 4886 4901 CTCAGAAGATGTTATC  19 2706 559509 4748 4763 4947 4962CAATTCACCAAGGAGC  10 2707 559510 4845 4860 5044 5059 CATATGCAGATAATGT 12 2708 559511 4976 4991 5175 5190 GACATTGCCTCTTCAT   4 2709 5595125041 5056 5240 5255 GTAGTGTAACATTTTC   3 2710 559513 5131 5146 5330 5345CGAAACATTGGCACAC  10 2711 559514 5142 5157 5341 5356 TCTGAGGCAAACGAAA 37 2712 559515 5229 5244 5428 5443 AAGTTAAACTTATCTG  38 2713 5595165257 5272 5456 5471 TATCCCTAACATGCAA  28 2714 559517 5359 5374 5558 5573CGATGGAAAAATTTCT  20 2715 559518 5466 5481 5665 5680 TTTAGAGGCTTTTAAG 60 2716 559519 5569 5584 5768 5783 GTAACATCTGATTCTA   9 2717 5595205721 5736 5920 5935 TGCCCCAACACTGAAC  42 2718 559521 5795 5810 5994 6009ATCCTGATCTGGTCCA  27 2719 559523 5830 5845 6029 6044 TCCTGCCTTAAAGTTA 61 2720 559525 5928 5943 6127 6142 GTCTAAGAGGTTATTT  29 2721 5595276061 6076 6260 6275 AGCATTTAAAGTTAAC  19 2722 559529 6169 6184 6368 6383GATGAAATGCCTCTGC  14 2723 559531 6259 6274 6458 6473 AACTCACTGCAAGGTC 15 2724 559533 6385 6400 6584 6599 ACCTGAAGTCAAGACA  18 2725 5595356532 6547 6731 6746 TCACTCAGCTGGATTT  16 2726 559537 6582 6597 6781 6796CAAATACGACTGCTTA  62 2727 559539 6849 6864 7048 7063 TGTTCCTGCATGTAAG 47 2728 559541 6964 6979 7163 7178 GTGGTTCCCAATCCCC  21 2729 5595437143 7158 7342 7357 CACATGCCAGTTACTC  12 2730 559545 7231 7246 7430 7445GTGCCTTTAGTGAGGG  23 2731 559547 7404 7419 7603 7618 GTACTTCAAGCATTCC  8 2732 559549 7519 7534 7718 7733 AGTGGTTGCCCGCTTT  16 2733 5595517748 7763 7947 7962 GCAAATTAATGGCCTT   8 2734 559553 7871 7886 8070 8085ATTACAGTTCTTGAAC  28 2735 559556 8158 8173 8357 8372 TGCCAACCACCAGCAT 81 2736 559557 8209 8224 8408 8423 GTCAAAGCAAAGACGC  82 2737 5595598378 8393 8577 8592 CGTGTAAATATGAATA  55 2738

TABLE 67 Inhibition of MALAT1 RNA by 3-10-3 cEt gapmers SEQ ID SEQ IDSEQ ID SEQ ID NO: 1 NO: 1 NO: 2824 NO: 2824 Compound Start Stop StartStop MALAT1 SEQ Number Site Site Site Site Sequence (5′ to 3′) (% UTC)ID No. 395240 3320 3339 3520 3539 TGCCTTTAGGATTCTAGACA  49   11 5560574700 4715 4899 4914 AGGCTGGTTATGACTC  10 2739 559522   84   99   50   65GTTGCTAAAATGGCGC  82 2740 559524  229  244  195  210 TGGAATGGCCAGCCTA 79 2741 559526  337  352  303  318 ATGAGCTTCAGACCTT  78 2742 559528 472  487  438  453 CGAATGGCTTTGTCTC  84 2743 559530  579  594  545  560GAAATTTTTCTACCGT  92 2744 559532  710  725  676  691 CACTCTTGGAAAACGC 91 2745 559534  816  831  782  797 CAGTCCTGCGACTTGC  98 2746 559536 918  933  884  899 GTGATAGTTCAGGGCT 103 2747 559538 N/A N/A 1001 1016GGTCATCAAACACCTC  70 2748 559540 N/A N/A 1110 1125 GGAACTTGAATGCAAA  752749 559542 N/A N/A 1200 1215 TCCGCCGCCTTTGTGA  69 2750 559544 1131 11461331 1346 CGGTTTCCTCAAGCTC   4 2751 559546 1326 1341 1526 1541CGTCATGTTTTAGAAA  11 2752 559548 1509 1524 1709 1724 CGCCTTCAAATTATTT  8 2753 5595501 1660 1675 1860 1875 AATTGTTTCATCCTAC  47 2754 5595521852 1867 2052 2067 ACATTTTGCCCTTAGC  10 2755 559554 2006 2021 2206 2221GTGCTATTTTATCCAA   4 2756 559555 2116 2131 2316 2331 GTAAACACCCTCATCT 27 2757 559558 2267 2282 2467 2482 TAAGGCCTTCCAAATT  27 2758 5595602448 2463 2648 2663 TCACTGAATCCACTTC  12 2759 559561 2576 2591 2776 2791CAAATCGCACTGGCTC  10 2760 559562 2679 2694 2879 2894 GCTACCTTCATCACCA 32 2761 559563 2758 2773 2958 2973 ACACTGGCATGCTGGT  20 2762 5595642839 2854 3039 3054 CCATAAGTAAGTTCCA   7   36 559565 2939 2954 3139 3154AAACCTACAACACCCG  26 2763 559566 2992 3007 3192 3207 GTCTGCCCTCAAAAGC 19 2764 559567 3063 3078 3263 3278 GTTTTCCTCAAATTCG   9 2765 5595683225 3240 3425 3440 AGTTACACATCCAAAC  22 2766 559569 3315 3330 3515 3530GATTCTAGACAGACCT  79 2767 559570 3370 3385 3570 3585 ATCCTGATATTGGATT 65 2768 559571 3467 3482 3667 3682 AACTACCAGCCATTTC  31 2769 5595723555 3570 3755 3770 ATCCCAAAATGCTTCA  22 2770 559573 3695 3710 3895 3910CAGTCCCTGAAGGTGT  20 2771 559574 3743 3758 3943 3958 ACTTTTCAGCTTCAAC 18 2772 559575 3814 3829 4014 4029 TTTGGCCTACTCAAGC  20 2773 5595774038 4053 4238 4253 GAGTTACTTGCCAACT  21 2774 559578 4131 4146 4331 4346GCCCAAATTAATGCAC  32 2775 559579 4232 4247 4432 4447 CCCAGTAGGCCAGACC 15 2776 559580 4350 4365 4550 4565 CAGTTTCTATAGTAGT  11 2777 5595814495 4510 4694 4709 GCAGTTAAACAATGGA   6 2778 559582 4624 4639 4823 4838AAAAGCCCACCCTCTA  60 2779 559583 4634 4649 4833 4848 CCTCATCAACAAAAGC 55 2780 559584 4798 4813 4997 5012 CTTATTCCCCAATGGA  14 2781 5595854899 4914 5098 5113 TGGTAGATTCCGTAAC   6 2782 559586 5004 5019 5203 5218GCTTTTGTAAAAGCAG  66 2783 559587 5092 5107 5291 5306 GATCCCAACTCATCTC  8 2784 559588 5136 5151 5335 5350 GCAAACGAAACATTGG   8 2785 5595895178 5193 5377 5392 AATGAAGCAACTCTTC  42 2786 559590 5250 5265 5449 5464AACATGCAATACTGCA   8 2787 559591 5303 5318 5502 5517 CCATGGTTGATATTTA 16 2788 559592 5411 5426 5610 5625 CTATCCCATCACTGAA  19 2789 5595935516 5531 5715 5730 AGATTCAATGCTAAAC  13 2790 559594 5658 5673 5857 5872GTATACATTCTCTAAT  52 2791 559595 5771 5786 5970 5985 TGTTCGCAGACAAAGT 14 2792 559596 5824 5839 6023 6038 CTTAAAGTTACATTCG   9 2793 5595975875 5890 6074 6089 GAATTATTATATGCTC  12 2794 559598 5994 6009 6193 6208TAGACCCCTGACTTTC   8 2795 559599 6111 6126 6310 6325 CCTATATAAGGTCAAT 39 2796 559600 6241 6256 6440 6455 ATACACTCACTAGAAC  55 2797 5596016327 6342 6526 6541 ACAAGTAAGCCCCACC  75 2798 559602 6428 6443 6627 6642GGATCAGAACAGTACT  15 2799 559603 6452 6467 6651 6666 TCACAATGCATTCTAA 28 2800 559604 6554 6569 6753 6768 TTTCCTCAACACTCAG  19 2801 5596056677 6692 6876 6891 AAAGACTAAAGGCTTC  19 2802 559606 6921 6936 7120 7135TTAAAGTAAATAGGCT  38 2803 559607 7032 7047 7231 7246 TTTTGTCCACTGGTGA 16 2804 559609 7303 7318 7502 7517 CTTAGGATAATAGCGC   6 2805 5596107454 7469 7653 7668 TAAGAGCTGCTATAAA  85 2806 559611 7641 7656 7840 7855CTGCATCGAGGTGAGG  19 2807 559612 7799 7814 7998 8013 AATAGAGCTACTTAGC 28 2808 559613 7974 7989 8173 8188 GAAAAAGTCTTAGCAG  33 2809 5596148054 8069 8253 8268 ACCTTCATGACCCTAC  65 2810 559615 8181 8196 8380 8395AACCCCGTCCTGGAAA  83 2811 559616 8316 8331 8515 8530 TAGTTCAAAGATATTG 93 2812 559617 8446 8461 8645 8660 GTAGGGCTTCTCAAAA 111 2813

Example 16: Dose-Dependent Inhibition of Human MALAT1 in A431 Cells by3-10-3 cEt Gapmers

Certain modified oligonucleotides described in the studies aboveexhibiting significant in vitro inhibition of MALAT1 RNA were selectedand tested at various doses in A431 cells in comparison with comparatorcompounds 395240, 395243, 395244, 395248, 395253, 395254, 395255,395256, 395280, 556089, and 559497 described above.

The modified oligonucleotides were tested in a series of experimentsusing the same culture conditions. The results for each experiment arepresented in separate tables shown below. Cultured A431 cells at adensity of 10,000 cells per well were transfected using free uptake withmodified oligonucleotides diluted to different concentrations asspecified in the tables below. After a treatment period of approximately48 hours, RNA levels were measured as previously described using theHuman primer-probe set RTS2736. MALAT1 RNA levels were normalized tototal RNA, as measured by RIBOGREEN®. Results are presented as percentchange of MALAT1 RNA, relative to PBS control.

The half maximal inhibitory concentration (IC₅₀) of each modifiedoligonucleotide was calculated using a linear regression on a log/linearplot of the data in excel and is also presented in the tables below. The% UTC values for modified oligonucleotides marked with a triple asteriskin the tables below has been previously presented in Example 3 (Table 3)herein above. The % UTC and IC₅₀ data for modified oligonucleotidesmarked with a triple asterisk (

) in the tables below is identical to the data presented in Example 3 asthe data is from the same experiments.

TABLE 68 Dose-dependent percent reduction of human MALAT1 RNA in A431cells by modified oligonucleotides Compound MALAT1 (% UTC) Number 0.4 nM2 nM 10 nM 50 nM 250 nM IC₅₀ nM 395240 177 217 122 22 4 57 395243 117 6574 86 23 92 395244 93 103 74 37 9 25 395248 106 110 95 44 17 50 395253103 90 79 20 8 19 395254 97 85 57 16 6 12 395255 67 84 81 60 29 98395256 110 93 85 26 7 23 395280 80 77 73 46 21 28 556089 112 79 103 4019 44 559497 90 94 75 40 11 25 559590 116 118 82 34 8 32

TABLE 69 Dose-dependent percent reduction of human MALAT1 RNA in A431cells by modified oligonucleotides Compound MALAT1 (% UTC) Number 0.4 nM2 nM 10 nM 50 nM 250 nM IC₅₀ nM  395240 93 77 46 19 10 9  395253 89 7431 8 6 6  395254 84 59 23 11 7 3  395256 87 77 48 24 7 9  556089 101 8571 34 14 22  559497 92 84 64 33 12 17  559564 85 67 30 8 2 4 1157124 9969 31 8 3 6 1157190 71 28 13 4 2 1 1157958 85 47 15 3 1 2 1157992 67 246 2 1 0.4 1158618 76 60 22 5 3 3

Example 17: Dose-Dependent Inhibition of Human MALAT1 in A431 Cells by3-10-3 cEt Gapmers

Certain modified oligonucleotides described in the studies aboveexhibiting significant in vitro inhibition of MALAT1 RNA were selectedand tested at various doses in A431 cells.

The modified oligonucleotides were tested in a series of experimentsusing the same culture conditions. The results for each experiment arepresented in separate tables shown below. Cultured A431 cells at adensity of 10,000 cells per well were transfected using free uptake withmodified oligonucleotides diluted to different concentrations asspecified in the tables below. After a treatment period of approximately48 hours, RNA levels were measured as previously described using theHuman primer-probe set RTS2736. MALAT1 RNA levels were normalized tototal RNA, as measured by RIBOGREEN®. Results are presented as percentchange of MALAT1 RNA, relative to PBS control.

The half maximal inhibitory concentration (IC₅₀) of each modifiedoligonucleotide was calculated using a linear regression on a log/linearplot of the data in excel and is also presented in the tables below. The% UTC values for modified oligonucleotides marked with a triple asteriskin the tables below has been previously presented in Example 3 (Table 3)herein above. The % UTC and IC₅₀ data for modified oligonucleotidesmarked with a triple asterisk (

) in the tables below is identical to the data presented in Example 3 asthe data is from the same experiments.

TABLE 70 Dose-dependent percent reduction of human MALAT1 RNA in A431cells by modified oligonucleotides Compound MALAT1 (% UTC) Number 0.3 nM1 nM 5 nM 20 nM IC₅₀ nM  559564 112 96 74 30 11 1156957 91 75 50 20 41157124 99 89 82 25 11 1157190 

89 93 58 18 6 1157191 140 99 69 29 9 1157224 102 110 88 35 20 1157525102 94 92 46 >20 1157826 137 113 101 86 >20 1157924 96 89 66 26 81157925 88 96 68 28 9 1157958 114 88 58 20 6 1157959 97 60 49 14 31157992 70 86 44 12 3 1157993 87 78 43 12 3 1158157 97 62 72 33 81158618 95 89 43 21 5 1158652 107 106 73 33 13 1158820 92 93 62 25 71158886 106 98 77 29 12

TABLE 71 Dose-dependent percent reduction of human MALAT1 RNA in A431cells by modified oligonucleotides Compound MALAT1 (% UTC) Number 0.3 nM1 nM 5 nM 20 nM IC₅₀ nM  559564 170 98 54 16 6 1156959 78 71 35 9 21156960 165 118 59 22 8 1156993 88 101 79 26 12 1157092 118 112 62 24 81157093 91 78 55 15 4 1157127 102 94 72 23 9 1157926 93 87 59 20 61157960 94 84 47 17 4 1157994 92 63 45 11 3 1158158 85 71 31 6 2 115815995 75 30 5 3 1158359 96 98 68 30 10 1158490 98 102 62 26 8 1158491 95 7033 6 3 1158492 84 52 14 3 1 1158622 144 129 70 22 10 1158821 98 76 50 154 1158855 123 129 104 38 >20

TABLE 72 Dose-dependent percent reduction of human MALAT1 RNA in A431cells by modified oligonucleotides Compound MALAT1 (% UTC) Number 0.3 nM1 nM 5 nM 20 nM IC₅₀ nM  559564 145 123 63 23 9 1157095 114 101 78 27 111157128 96 130 83 37 >20 1157130 101 90 63 18 6 1157431 82 66 63 46 141157597 121 84 58 16 6 1157831 94 90 67 28 9 1157895 102 113 88 56 >201157928 104 106 76 33 13 1157929 

81 76 29 10 2 1158161 

83 77 37 9 3 1158162 

82 78 32 10 3 1158227 83 86 61 24 6 1158228 106 91 56 25 7 1158429 144101 60 29 8 1158459 113 114 104 52 >20 1158623 79 82 56 24 5 1158789 107121 98 43 >20 1158857 105 107 60 23 8

TABLE 73 Dose-dependent percent reduction of human MALAT1 RNA in A431cells by modified oligonucleotides Compound MALAT1 (% UTC) Number 0.3 nM1 nM 5 nM 20 nM IC₅₀ nM  559564 151 92 57 19 6 1156996 96 87 51 24 61157096 107 112 66 45 18 1157097 79 70 39 9 2 1157131 59 67 36 10 11157366 87 82 39 10 3 1157697 73 80 51 19 4 1157698 71 41 36 13 11157897 98 102 66 29 10 1157931 101 84 47 13 4 1158000 146 83 74 25 81158163 103 84 41 12 4 1158164 97 81 45 11 4 1158230 78 62 31 10 21158231 115 82 53 21 5 1158263 102 99 68 28 9 1158495 104 90 42 12 41158625 80 68 48 21 3 1158859 99 96 58 18 6

TABLE 74 Dose-dependent percent reduction of human MALAT1 RNA in A431cells by modified oligonucleotides Compound MALAT1 (% UTC) Number 0.3 nM1 nM 5 nM 20 nM IC₅₀ nM  559564 115 91 44 14 5 1157032 86 103 35 8 51157033 93 67 43 27 4 1157064 86 75 43 16 3 1157065 93 75 56 21 51157099 89 78 55 25 5 1157534 79 75 62 36 9 1157535 105 90 45 19 51157600 93 100 45 14 5 1157701 102 96 61 18 6 1157898 89 88 59 23 61158001 85 106 74 35 12 1158002 90 73 34 10 3 1158067 88 79 54 23 51158165 93 68 27 7 2 1158232 79 80 61 21 5 1158431 107 89 74 32 111158497 94 95 56 20 6 1158626 79 86 56 36 9

TABLE 75 Dose-dependent percent reduction of human MALAT1 RNA in A431cells by modified oligonucleotides Compound MALAT1 (% UTC) Number 0.3 nM1 nM 5 nM 20 nM IC₅₀ nM  559564 143 83 48 15 5 1157001 100 76 36 8 31157034 

72 57 26 6 1 1157035 115 89 46 11 4 1157101 95 83 48 13 4 1157102 113 6525 8 3 1157836 95 83 56 28 6 1157900 105 93 51 19 5 1157901 56 83 62 166 1157902 109 86 34 13 4 1157934 108 80 46 11 4 1157936 91 59 24 5 21157969 119 96 53 17 6 1157970 89 60 19 5 2 1158003 89 82 43 10 31158004 90 62 30 7 2 1158069 88 78 47 19 4 1158167 95 88 51 15 5 115816884 63 33 9 2

TABLE 76 Dose-dependent percent reduction of human MALAT1 RNA in A431cells by modified oligonucleotides Compound MALAT1 (% UTC) Number 0.3 nM1 nM 5 nM 20 nM IC₅₀ nM  559564 135 84 58 17 6  946404 107 73 44 12 41157036 99 76 42 21 4 1157103 95 86 56 30 7 1157171 129 89 41 11 51157571 128 101 80 24 10 1157703 91 84 50 23 5 1157871 94 87 48 17 51157938 95 69 38 11 3 1157971 83 60 16 5 2 1157972 93 71 22 7 2 115800598 68 24 7 2 1158135 88 91 63 29 8 1158136 63 80 46 19 5 1158137 85 6728 9 2 1158170 87 72 33 10 3 1158236 99 102 78 34 12 1158435 120 91 5925 7 1158631 99 112 81 70 >20

TABLE 77 Dose-dependent percent reduction of human MALAT1 RNA in A431cells by modified oligonucleotides Compound MALAT1 (% UTC) Number 0.3 nM1 nM 5 nM 20 nM IC₅₀ nM  559564 129 95 55 18 6 1157139 89 69 44 14 31157306 104 61 63 17 5 1157474 148 129 78 28 11 1157575 102 61 29 9 31157807 85 77 77 31 11 1157872 117 104 57 20 7 1157905 117 91 47 22 61157940 121 88 43 12 5 1157973 108 87 34 7 4 1157974 128 106 47 12 61158006 94 77 44 16 4 1158138 91 80 44 14 4 1158139 93 66 25 7 2 1158171102 81 28 8 3 1158172 95 72 38 12 3 1158337 97 84 43 14 4 1158338 96 9257 17 5 1158568 117 77 47 18 5

TABLE 78 Dose-dependent percent reduction of human MALAT1 RNA in A431cells by modified oligonucleotides Compound MALAT1 (% UTC) Number 0.3 nM1 nM 5 nM 20 nM IC₅₀ nM  559564 132 103 68 22 8 1157009 151 100 54 23 71157108 114 74 30 9 3 1157109 137 78 52 16 5 1157142 111 96 88 28 131157150 107 100 74 35 13 1157207 129 102 65 22 8 1157750 122 113 9258 >20 1157841 111 93 68 43 14 1157941 102 85 44 17 4 1157942 113 96 7219 8 1157943 142 102 67 20 8 1158140 89 68 31 12 2 1158141 100 97 16 284 1158373 108 105 79 41 19 1158569 123 84 44 15 5 1158570 96 82 58 18 51158736 111 97 79 39 16 1158737 135 113 76 43 15

TABLE 79 Dose-dependent percent reduction of human MALAT1 RNA in A431cells by modified oligonucleotides Compound MALAT1 (% UTC) Number 0.3 nM1 nM 5 nM 20 nM IC₅₀ nM  559564 138 125 74 32 12 1156942 108 91 71 30 101157042 93 102 93 72 20 1157044 116 93 64 19 7 1157075 85 87 64 28 81157076 134 113 80 32 12 1157077 103 102 82 26 10 1157110 107 93 50 13 51157111 

108 73 6 7 2 1157279 127 111 99 74 >20 1157478 134 114 74 13 8 1157546200 149 107 40 17 1157644 90 94 60 24 7 1157711 74 109 75 32 11 1157712128 93 51 19 6 1158012 111 101 90 44 27 1158142 113 111 75 23 10 1158175105 112 109 130 20 1158738 98 92 72 30 10

TABLE 80 Dose-dependent percent reduction of human MALAT1 RNA in A431cells by modified oligonucleotides Compound MALAT1 (% UTC) Number 0.3 nM1 nM 5 nM 20 nM IC₅₀ nM  559564 127 129 73 27 10 1156978 112 106 71 4517 1157179 104 93 65 36 10 1157180 95 94 60 31 9 1157181 124 78 45 13 41157246 93 91 72 32 11 1157247 104 107 78 42 20 1157282 128 98 62 25 81157448 96 92 20 23 4 1157612 96 99 57 43 12 1157780 97 110 81 34 121157880 102 100 69 41 15 1157912 87 92 52 19 5 1157946 112 97 68 37 111157947 93 91 50 15 5 1158013 95 104 97 56 >20 1158312 96 99 77 33 131158541 102 96 68 43 16 1158839 95 81 82 44 >20

TABLE 81 Dose-dependent percent reduction of human MALAT1 RNA in A431cells by modified oligonucleotides Compound MALAT1 (% UTC) Number 0.3 nM1 nM 5 nM 20 nM IC₅₀ nM  559564 145 127 69 22 9 1157014 99 83 62 23 61157016 85 70 39 10 3 1157048 99 73 12 11 2 1157080 90 76 47 15 41157081 88 78 43 13 3 1157251 115 78 51 16 5 1157450 100 82 43 16 41157718 131 90 54 15 6 1157782 98 79 46 14 4 1157915 95 101 49 15 61157948 110 92 60 18 6 1157951 102 74 29 8 3 1157982 83 78 37 15 31157983 87 80 41 8 3 1158381 113 88 74 35 11 1158809 87 92 46 11 41158810 90 53 20 5 2 1158812 86 49 13 3 1

TABLE 82 Dose-dependent percent reduction of human MALAT1 RNA in A431cells by modified oligonucleotides Compound MALAT1 (% UTC) Number 0.3 nM1 nM 5 nM 20 nM IC₅₀ nM  559564 129 101 66 25 8  568503 95 78 21 21 31156951 94 84 47 14 4 1157153 102 91 64 25 7 1157185 156 109 65 23 81157186 85 83 44 15 4 1157318 96 97 73 41 18 1157454 81 81 36 11 31157519 105 101 75 36 14 1157752 110 61 39 12 3 1157886 95 101 48 15 61157919 95 89 34 10 3 1157953 109 94 46 13 5 1157987 93 82 38 12 31158051 113 120 137 81 20 1158084 112 93 60 30 8 1158183 90 84 51 20 51158645 107 98 49 22 6 1158814 98 88 66 23 7

TABLE 83 Dose-dependent percent reduction of human MALAT1 RNA in A431cells by modified oligonucleotides Compound MALAT1 (% UTC) Number 0.3 nM1 nM 5 nM 20 nM IC₅₀ nM  559564 142 106 57 17 7 1156950 97 78 47 15 41157015 94 80 37 11 3 1157017 89 75 43 11 4 1157084 82 86 51 12 31157518 74 71 29 9 4 1157717 87 66 27 9 7 1157754 99 82 54 19 7 115778395 83 58 12 2 1157918 96 76 40 9 3 1157920 131 79 41 11 3 1157950 94 7810 8 2 1157984 50 59 28 4 2 1158021 174 131 60 19 2 1158150 85 82 53 145 1158614 82 45 16 3 1 1158780 85 99 67 19 5 1158811 105 65 40 8 41158813 100 110 67 12 8

TABLE 84 Dose-dependent percent reduction of human MALAT1 RNA in A431cells by modified oligonucleotides Compound MALAT1 (% UTC) Number 0.3 nM1 nM 5 nM 20 nM IC₅₀ nM  559564 179 119 67 17 8 1156954 93 85 59 25 61156987 118 80 39 7 4 1156988 113 81 52 17 5 1157021 106 86 17 24 41157188 106 93 58 28 8 1157290 115 81 71 27 8 1157489 100 88 35 6 31157922 91 90 63 19 7 1157954 98 82 48 18 5 1158055 103 85 43 10 41158056 91 80 57 24 6 1158186 77 82 57 22 6 1158187 98 84 45 12 41158285 90 73 57 24 5 1158386 119 92 56 13 6 1158388 134 137 87 29 121158615 93 43 8 1 1 1158616 93 83 49 17 4

TABLE 85 Dose-dependent percent reduction of human MALAT1 RNA in A431cells by modified oligonucleotides Compound MALAT1 (% UTC) Number 0.3 nM1 nM 5 nM 20 nM IC₅₀ nM  395254 112 67 73 35 10  559564 146 119 84 30 121156481 109 103 87 87 20 1156989 83 85 59 25 7 1157123 128 112 58 32 91157223 99 88 54 24 6 1157357 95 95 70 82 20 1157524 105 103 52 15 61157726 106 86 69 36 11 1157756 102 86 86 45 >20 1157923 89 83 24 18 31157957 82 96 38 17 5 1157991 88 80 25 4 2 1158090 128 118 115 59 201158255 90 84 74 26 9 1158487 115 91 74 22 8 1158585 62 78 47 17 41158717 80 97 80 66 20 1158851 89 84 95 83 20

Example 18: Dose-Dependent Inhibition of Human MALAT1 in MDA-MB-436Cells by cEt Gapmers

Modified oligonucleotides described in the studies above were tested atvarious doses in MDA-MB-436 cells. Cultured MDA-MB-436 cells at adensity of 5,000-12,000 cells per well were treated using free uptakewith modified oligonucleotides diluted to concentrations described inthe tables below. After approximately 48 hours, MALAT1 RNA levels weremeasured as previously described using the Human MALAT1 primer-probe setRTS2736. MALAT1 RNA levels were normalized to b-actin, measured usinghuman primer-probe set HTS5002 (described herein above). Results arepresented in the tables below as percent control of the amount of MALAT1RNA relative to untreated control cells (% UTC). IC50s were calculatedusing the “log(inhibitor) vs. response—variable slope (4 parameters)”formula using Prism6 software. The % UTC values for modifiedoligonucleotides marked with a triple asterisk in the tables below hasbeen previously presented in Example 4 (Table 4) herein above. The % UTCdata for modified oligonucleotides marked with a triple asterisk (

) in the tables below is identical to the data presented in Table 4 asthe data is from the same experiments.

TABLE 86 Dose-dependent inhibition of human MALAT1 RNA expression bymodified oligonucleotides in MDA-MB-436 cells Compound % control IC50Number 0.8 nM 4.0 nM 20.0 nM 100.0 nM (nM)  559564 105 93 54 12 22.9 568503 90 76 34 20 12.2 1157044 138 84 51 20 22.9 1157131 102 52 47 69.6 1157150 92 80 53 27 25.0 1157190 

56 39 15 5 1.4 1157726 82 58 53 14 11.1 1157929 

58 51 33 5 2.6 1157936 34 30 18 6 0.2 1157943 64 49 39 10 3.6 1157958 5032 21 6 0.9 1157959 83 52 27 5 4.9 1157992 51 44 9 2 1.2 1157993 67 2814 3 1.6 1158002 49 62 49 12 3.7 1158005 49 34 17 3 0.8 1158161 

36 48 27 3 0.5 1158230 65 57 63 12 8.9 1158263 61 59 52 29 9.3 115849078 54 32 15 5.7 1158491 58 40 20 9 1.6 1156959 68 55 33 6 4.2 1158618 5655 28 9 2.6 1158821 50 53 28 8 1.8 1158886 58 57 53 21 6.4 1157021 70 4650 19 5.8 1157032 94 51 20 3 4.8 1157034 

50 25 17 5 0.7 1157048 57 41 28 9 1.7 1157097 56 63 27 4 3.2 1157108 5137 18 3 1.0 1157110 51 48 17 5 1.4 1157111 

98 30 13 8 2.9 1157181 104 56 30 7 7.0 1157448 77 89 43 17 16.8 1157575101 64 21 6 6.8 1157698 99 81 51 16 20.0 1157752 77 89 49 11 18.21157912 43 61 32 12 1.6 1157919 84 38 32 5 3.8 1157923 72 53 34 8 4.61157947 90 61 27 6 6.6 1157950 108 104 48 12 20.2 1157951 106 85 33 612.8 1157970 59 58 24 4 3.0 1157971 57 40 19 4 1.5 1157972 91 34 10 32.8 1157973 71 55 11 2 3.3 1157974 83 72 24 5 7.7 1157984 80 74 52 1315.1 1157991 67 65 19 2 4.3 1158004 68 57 26 3 4.0 1158056 52 99 67 2334.9 1158137 65 37 35 4 2.3 1158139 62 59 35 10 4.4 1158140 59 67 38 105.4 1158159 112 85 27 10 11.6 1158162 

57 37 22 6 1.5 1158163 118 51 16 7 4.0 1158164 90 52 19 6 4.7 1158165 7936 10 3 2.5 1158168 45 37 19 6 0.7 1158171 78 31 16 6 2.4 1158492 41 2912 5 0.4 1158614 45 36 26 8 0.6 1158615 31 19 14 6 0.1 1158810 40 23 114 0.4 1158812 47 29 15 2 0.7

Example 19: Tolerability of Modified Oligonucleotides Targeting HumanMALAT1 in CD-1 Mice

BALB/c mice are a multipurpose mouse model frequently utilized forsafety and efficacy testing. The mice were treated with modifiedoligonucleotides selected from studies described above and evaluated forchanges in the levels of various plasma chemistry markers.

Study 1

Groups of four 6-to-8-week-old male BALB/c mice were injectedsubcutaneously twice a week for 4 weeks (for a total of 8 treatments)with 50 mg/kg of modified oligonucleotides. One group of four male CD-1mice was injected with PBS. Mice were euthanized 24 hours following thefinal administration.

To evaluate the effect of modified oligonucleotides on liver and kidneyfunction, plasma levels of aspartate aminotransferase (AST), alanineaminotransferase (ALT), total bilirubin (TBIL), and blood urea nitrogen(BUN) were measured using an automated clinical chemistry analyzer(Hitachi Olympus AU400c, Melville, N.Y.). The results are presented inthe table below. Assays include four animals in a group, except where anasterisk (*) indicates that 3 animals or less was used for a specificassay. Modified oligonucleotides that caused changes in the levels ofany of the liver or kidney function markers outside the expected rangefor modified oligonucleotides were excluded in further studies.

TABLE 87 Plasma chemistry markers in male BALB/c mice Compound ALT ASTBUN Number (IU/L) (IU/L) (mg/dL) PBS 126 112 23 556057 6377 4060 29556089 120 127 19 559479 511 521 24 559482 65 89 25 559484 2728 1760 24559497* 43 72 28 559509 2535 2366 28 559511 2226 1626 25 559512 304 26128 559519 912 470 24 559547 2213 839 32 559548 3279 1520 28 559551 374215 21 559554 1921 1649 24 559564 88 116 24 559567 2832 5557 24 5595811301 842 23 559585 1038 1053 25 559587 716 490 24 559588 2706 2201 18559590* 195 158 24 559596 51 114 24 559598 1301 999 25 559609* 390 35624

Body weight was measured on day 25, and the average body weight for eachgroup is presented in the table below. Liver, kidney and spleen weightswere measured at the end of the study and are presented in the tablebelow. Modified oligonucleotides that caused any changes in organweights outside the expected range for modified oligonucleotides wereexcluded from further studies.

TABLE 88 Body and organ weights (in grams) Compound Body Weight LiverKidney Spleen Number (g) (g) (g) (g) PBS 25 1.3 0.4 0.1 556057 20 2.20.3 0.1 556089 25 1.7 0.4 0.1 559479 24 1.8 0.4 0.1 559482 26 1.5 0.40.2 559484 26 2.1 0.4 0.2 559497* 24 1.3 0.4 0.1 559509 25 1.2 0.4 0.1559511 22 1.4 0.3 0.1 559512 25 1.7 0.4 0.1 559519 24 1.8 0.3 0.1 55954720 1 0.3 0.1 559548 25 3.4 0.3 0.2 559551 23 1.2 0.3 0.1 559554 27 2.20.4 0.2 559564 25 1.5 0.4 0.2 559567 17 1 0.3 0 559581 23 1.7 0.3 0.1559585 24 1.6 0.4 0.1 559587 26 2.2 0.4 0.2 559588 22 1.4 0.3 0.2559590* 26 1.9 0.4 0.2 559596 24 1.4 0.4 0.1 559598 25 1.9 0.4 0.1559609 25 1.8 0.4 0.3Study 2

Groups of four 4-to-6-week-old male CD-1 mice were injectedsubcutaneously twice a week for 4 weeks (for a total of 8 treatments)with 50 mg/kg/dose of modified oligonucleotides. One group of four maleCD-1 mice was injected with PBS. Mice were euthanized 24 hours followingthe final administration. The values for modified oligonucleotidesmarked with a triple asterisk in the tables below have been previouslypresented in Tables 7 and 8 herein above. The data for modifiedoligonucleotides marked with a triple asterisk (

) in the tables below is identical to the data presented in Table 7 andTable 8 as the data is from the same experiments.

To evaluate the effect of modified oligonucleotides on liver and kidneyfunction, plasma levels of alanine aminotransferase (ALT), aspartateaminotransferase (AST), blood urea nitrogen (BUN), total bilirubin(TBIL), and albumin (ALB) were measured using an automated clinicalchemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.). The resultsare presented in the table below. Assays include four animals in agroup, except where an asterisk (*) indicates that 3 animals or less wasused for a specific assay. Modified oligonucleotides that caused changesin the levels of any of the liver or kidney function markers outside theexpected range for modified oligonucleotides were excluded in furtherstudies.

TABLE 89 Plasma chemistry markers in CD-1 Male mice Compound ALT AST BUNTBIL ALB Number (IU/L) (IU/L) (mg/dL) (mg/dL) (g/dL) PBS  20  46 24 0.22.5 1157190  78  95 26 0.2 2.6 1157919 388 269 30 0.3 2.3 1157929 

330 225 24 0.2 2.3 1157936 220 171 25 0.2 2.2 1157958  38  50 22 0.2 2.41157970 195 250 25 6.1 3.1 1157972 1172  824 23 2.9 2.9 1157991 343 26425 0.2 2.2 1157992 1168  2608  18 1.9 2.5 1157993 630 545 23 0.2 1.91158002 963 737 26 0.2 2.2 1158005 115 149 25 0.2 1.9 1158161 

 86 128 29 0.2 2.3 1158162 178 199 25 0.2 2.5 1158491 598 684 24 0.2 2.21158492 451 417 20 0.2 1.9 1158810 1589* 1409*  37* 0.3* 2.3* 11588124795* 4273*  30* 1.4* 4.5*

Body weights of CD-1 mice were measured at the end of the study, and theaverage body weight for each group is presented in the table below.Liver, kidney and spleen weights were measured at the end of the studyand are presented in the table below. Modified oligonucleotides thatcaused any changes in organ weights outside the expected range formodified oligonucleotides were excluded from further studies.

TABLE 90 Body and organ weights (in grams) Compound Body Weight LiverKidney Spleen Number (g) (g) (g) (g) PBS 32 1.7 0.5 0.1 1157190 36 2.20.5 0.2 1157919 38 2.9 0.5 0.4 1157929 

34 2.3 0.5 0.2 1157936 33 2 0.5 0.1 1157958 35 2.1 0.5 0.2 1157970 312.2 0.4 0.2 1157972 31 2.7 0.5 0.2 1157991 37 2.6 0.5 0.2 1157992 29 2.30.5 0.1 1157993 37 2.7 0.6 0.3 1158002 31 2.2 0.5 0.2 1158005 35 2.2 0.50.2 1158161 

34 2.3 0.5 0.2 1158162 34 2.3 0.6 0.2 1158491 34 2.1 0.5 0.2 1158492 362.1 0.5 0.2 1158810 28 1.7 0.4 0.1 1158812 27 2 0.4 0.1Study 3

Groups of four 4-to-6-week-old male CD-1 mice were injectedsubcutaneously twice a week for 4 weeks (for a total of 8 treatments)with 50 mg/kg/dose of modified oligonucleotides. One group of four maleCD-1 mice was injected with PBS. Mice were euthanized 24 hours followingthe final administration.

To evaluate the effect of modified oligonucleotides on liver and kidneyfunction, plasma levels of alanine aminotransferase (ALT), aspartateaminotransferase (AST), blood urea nitrogen (BUN), and total bilirubin(TBIL) were measured using an automated clinical chemistry analyzer(Hitachi Olympus AU400c, Melville, N.Y.). The results are presented inthe table below. Assays include four animals in a group, except where anasterisk (*) indicates that 3 animals or less was used for a specificassay. Modified oligonucleotides that caused changes in the levels ofany of the liver or kidney function markers outside the expected rangefor modified oligonucleotides were excluded in further studies.

The values for modified oligonucleotides marked with a triple asteriskin the tables below have been previously presented in Tables 13 and 14herein above. The data for modified oligonucleotides marked with atriple asterisk (

) in the tables below is identical to the data presented in Table 13 andTable 14 as the data is from the same experiments

TABLE 91 Plasma chemistry markers in CD-1 Male mice ALT AST BUN TBIL IONNO. (IU/L) (IU/L) (mg/dL) (mg/dL) PBS 20 51 21 0.2 1157032 1933 746 200.1 1304893 52 106 19 0.2 1157919 389 271 30 0.2 1304889 57 80 25 0.21157936 86 87 18 0.2 1304906 

59 78 22 0.2 1157970 224 305 21 0.2 1304890 

33 51 21 0.2 1157972 1477 785 28 0.3 1304888 59 94 21 0.2 1157993 455428 20 0.2 1304903 194 157 19 0.2 1158002 861 734 26 0.1 1304883 203 27126 0.2 1158162 240 243 24 0.2 1304898 310 335 24 0.2 1158491 131 155 270.2 1304900 61 140 27 0.3 1158492 422 358 20 0.2 1304899 66 96 21 0.21158812 3116 2358 25 0.5 1304895 35 98 24 0.2 1158139 326 256 22 0.21304882 1931 797 23 0.2 1158168 1492 880 31 0.2 1304901 1790 1477 34 4.31157974 1664 1935 23 2.5 1304885 98 107 18 0.2

Body weights of CD-1 male mice were measured at days 1 and 25, and theaverage body weight for each group is presented in the table below.Liver, kidney and spleen weights were measured at the end of the studyand are presented in the table below. Modified oligonucleotides thatcaused any changes in organ weights outside the expected range formodified oligonucleotides were excluded from further studies.

TABLE 92 Body and organ weights (in grams) Body Weight Liver KidneySpleen ION No. (g) (g) (g) (g) PBS 32 1.6 0.5 0.1 1157032 32 2 0.5 0.21304893 35 2 0.5 0.1 1157919 34 2.4 0.4 0.2 1304889 35 1.9 0.5 0.21157936 38 2.1 0.6 0.1 1304906 

34 1.8 0.5 0.1 1157970 33 2.2 0.4 0.2 1304890 

36 2 0.5 0.2 1157972 30 2.4 0.4 0.1 1304888 35 1.9 0.5 0.1 1157993 362.5 0.5 0.3 1304903 36 2.3 0.5 0.2 1158002 34 2.1 0.5 0.2 1304883 35 20.6 0.2 1158162 35 2 0.5 0.1 1304898 37 2.4 0.6 0.2 1158491 36 2.1 0.50.2 1304900 34 1.9 0.6 0.3 1158492 36 2 0.6 0.2 1304899 35 2 0.5 0.21158812 27 1.9 0.4 0.1 1304895 37 1.9 0.5 0.2 1158139 34 2.6 0.5 0.11304882 32 3.1 0.5 0.1 1158168 37 5.4 0.5 0.2 1304901 32 5 0.5 0.21157974 26 1.2 0.5 0.1 1304885 36 2.3 0.6 0.2Study 4

Groups of four 4-to-6-week-old male CD-1 mice were injectedsubcutaneously twice a week for 4 weeks (for a total of 8 treatments)with 50 mg/kg/dose of modified oligonucleotides. One group of four maleCD-1 mice was injected with PBS. Mice were euthanized 72 hours followingthe final administration. The values for modified oligonucleotidesmarked with a triple asterisk in the tables below have been previouslypresented in Tables 15 and 16 herein above. The data for modifiedoligonucleotides marked with a triple asterisk (

) in the tables below is identical to the data presented in Table 15 andTable 16 as the data is from the same experiments.

To evaluate the effect of modified oligonucleotides on liver and kidneyfunction, plasma levels of alanine aminotransferase (ALT), aspartateaminotransferase (AST), blood urea nitrogen (BUN), and total bilirubin(TBIL) were measured using an automated clinical chemistry analyzer(Hitachi Olympus AU400c, Melville, N.Y.). The results are presented inthe table below. Assays include four animals in a group, except where anasterisk (*) indicates that 3 animals or less was used for a specificassay. Modified oligonucleotides that caused changes in the levels ofany of the liver or kidney function markers outside the expected rangefor modified oligonucleotides were excluded in further studies.

TABLE 93 Plasma chemistry markers in CD-1 Male mice Compound ALT AST BUNTBIL Number (IU/L) (IU/L) (mg/dL) (mg/dL) PBS 19 56 16 0.2 1304879 36 4814 0.1 1304880 129  153  16 0.1 1304881 103  80 14 0.2 1304884 

33 55 15 0.1 1304886 27 71 17 0.1 1304887 1531  1672  20 1.5 1304891242  143  17 0.1 1304892 79 94 17 0.2 1304894 1009  569  19 0.2 130489651 54 15 0.2 1304897  99* 106*  16* 0.1* 1304902 34 47 16 0.1 1304904 2952 15 0.1 1304905 737  389  16 0.1 1304907 102  84 14 0.1 1304908 71 6917 0.1

Body weights of CD-1 male mice were measured at days 1 and 25, and theaverage body weight for each group is presented in the table below.Liver, kidney and spleen weights were measured at the end of the studyand are presented in the table below. Modified oligonucleotides thatcaused any changes in organ weights outside the expected range formodified oligonucleotides were excluded from further studies.

TABLE 94 Body and organ weights (in grams) Compound Body Weight LiverKidney Spleen Number (g) (g) (g) (g) PBS 34 2 0.5 0.1 1304879 34 2.2 0.50.1 1304880 36 2.5 0.5 0.2 1304881 34 2.2 0.5 0.2 1304884 

37 2.2 0.5 0.2 1304886 38 2.2 0.6 0.1 1304887 33 2.9 0.4 0.1 1304891 373.2 0.5 0.2 1304892 35 2.3 0.5 0.2 1304894 33 1.7 0.4 0.1 1304896 35 2.10.5 0.1 1304897 35 2.2* 0.5* 0.2* 1304902 39 2.4 0.6 0.2 1304904 37 2.20.5 0.2 1304905 38 2.6 0.5 0.2 1304907 36 1.9 0.5 0.1 1304908 37 2.3 0.60.3Study 5

Groups of four 4-to-6-week-old male CD-1 mice were injectedsubcutaneously twice a week for 4 weeks (for a total of 8 treatments)with 50 mg/kg/dose of modified oligonucleotides. One group of four maleCD-1 mice was injected with PBS. Mice were euthanized 24 hours followingthe final administration. The values for modified oligonucleotidesmarked with a triple asterisk in the tables below have been previouslypresented in Tables 9 and 10 herein above. The data for modifiedoligonucleotides marked with a triple asterisk (

) in the tables below is identical to the data presented in Table 9 andTable 10 as the data is from the same experiments.

To evaluate the effect of modified oligonucleotides on liver and kidneyfunction, plasma levels of alanine aminotransferase (ALT), aspartateaminotransferase (AST), blood urea nitrogen (BUN) and total bilirubin(TBIL) were measured using an automated clinical chemistry analyzer(Hitachi Olympus AU400c, Melville, N.Y.). The results are presented inthe table below. Assays include four animals in a group, except where anasterisk (*) indicates that 3 animals or less was used for a specificassay. Modified oligonucleotides that caused changes in the levels ofany of the liver or kidney function markers outside the expected rangefor modified oligonucleotides were excluded in further studies.

TABLE 95 Plasma chemistry markers in CD-1 Male mice Compound ALT AST BUNTBIL Number (IU/L) (IU/L) (mg/dL) (mg/dL) PBS  43  71 26 0.2 1157034 891641 23 0.2 1157032 579 652 20 0.2 1157048 2247  2324  20 4.2 11571101408  966 25 0.3 1157111 

341 200 22 0.2 1158139 651 307 25 0.2 1158614 8358* 6909*  37* 4.6*1158615 1699  1170  30 0.3 1158168 3846  1734  27 10.7 1157974 1399 1957   16* 1.1

Body weights of CD-1 male mice were measured at days 1 and 25, and theaverage body weight for each group is presented in the table below.Liver, kidney and spleen weights were measured at the end of the studyand are presented in the table below. Modified oligonucleotides thatcaused any changes in organ weights outside the expected range formodified oligonucleotides were excluded from further studies.

TABLE 96 Body and organ weights (in grams) Compound Body Weight LiverKidney Spleen Number (g) (g) (g) (g) PBS 37 2 0.6 0.1 1157032 35 2.3 0.40.2 1157034 33 2 0.4 0.1 1157048 31 2.7 0.4 0.1 1157110 32 1.8 0.5 0.21157111 

38 2.8 0.5 0.2 1157974 30 1.6 0.5 0.2 1158139 34 3 0.4 0.1 1158168 315.1 0.4 0.1 1158614 27 3.2 0.4 0 1158615 26 1.6 0.3 0.1

Example 20: Tolerability of Modified Oligonucleotides Targeting HumanMALAT1 in Sprague-Dawley Rats

Sprague-Dawley rats are a multipurpose model used for safety andefficacy evaluations. The rats were treated with Ionis modifiedoligonucleotides from the studies described in the Examples above andevaluated for changes in the levels of various plasma chemistry markers.

Study 1

Groups of 4 Sprague-Dawley rats each were weekly injected subcutaneouslywith 50 mg/kg of Ionis oligonucleotide for 6 weeks (total 7 doses). Therats were euthanized; and organs, urine and plasma were harvested forfurther analysis 2 days after the last dose.

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver and kidneyfunction, plasma levels of alanine aminotransferase (ALT), aspartateaminotransferase (AST), blood urea nitrogen (BUN) and total bilirubin(TBIL) were measured using an automated clinical chemistry analyzer(Hitachi Olympus AU400c, Melville, N.Y.). The results are presented inthe table below. Assays include four animals in a group, except where anasterisk (*) indicates that 3 animals or less was used for a specificassay. Modified oligonucleotides that caused changes in the levels ofany of the liver or kidney function markers outside the expected rangefor modified oligonucleotides were excluded in further studies.

TABLE 97 Plasma chemistry markers in Sprague-Dawley rats Compound ALTAST BUN TBIL Number (IU/L) (IU/L) (mg/dL) (mg/dL) PBS 65 133 16 0.71157034* 333 292 195 0.8 1157111 37 73 31 0.2 1157190 47 83 19 0.21157929 42 74 20 0.2 1158161 92 117 22 0.2 1158162 882 700 96 1.7

Blood obtained from rat groups at the end of the study, day 43, weresent to IDEXX BioAnalytics for measurement of blood cell counts. Countstaken include red blood cell (RBC) count, Hemoglobin (HGB), Hematocrit(HCT), platelet count (PLT), total white blood cell count (WBC),neutrophil counts (NEU), lymphocyte counts (LYM), and monocyte counts(MON). The results are presented in the tables below. Ionisoligonucleotides that caused changes in the blood cell count outside theexpected range for modified oligonucleotides were excluded in furtherstudies.

TABLE 98 Blood Cell Count in Sprague-Dawley Rats Compound RBC HGB HCTPLT WBC NEU LYM MON No. (×106/μL) (g/dL) (%) (10³/μL) (×10³/μL) (%) (%)(%) PBS 8 15 44 667 8 18 75 5 1157034* 6 11 32 836 15 42 53 5 1157111 611 34 677 17 32 62 5 1157190 6 12 35 632 10 19 76 4 1157929 7 12 36 7719 25 69 5 1158161 7 13 36 1068 10 28 65 7 1158162 7 11 33 743 21 33 60 7

To evaluate the effect of Ionis oligonucleotides on kidney function,urinary levels of micro total protein (MTP) and creatinine were measuredusing an automated clinical chemistry analyzer (Hitachi Olympus AU400c,Melville, N.Y.). The ratios of MTP to creatinine (MTP/C ratio) arepresented in the table below. Ionis oligonucleotides that caused changesin the levels of the ratio outside the expected range for modifiedoligonucleotides were excluded in further studies.

TABLE 99 MTP to creatinine ratio in Sprague-Dawley rats Compound MTP/CNumber Ratio PBS 3 1157034* 837 1157111 77 1157190 11 1157929 15 115816113 1158162 161

Body weights of rats were measured at on day 41, and the average bodyweight for each group is presented in the table below. Liver, spleen andkidney weights were measured at the end of the study, and are presentedin the table below. Ionis oligonucleotides that caused any changes inorgan weights outside the expected range for modified oligonucleotideswere excluded from further studies.

TABLE 100 Body and organ weights (g) Compound Body Weight Liver KidneySpleen Number (g) (g) (g) (g) PBS 469 17 3.5 1.1 1157034* 338 13 7.1 1.31157111 348 16 3.2 1.8 1157190 358 16 3.7 2.2 1157929 389 16 3.2 1.81158161 422 16 3.3 1.7 1158162 306 13 4.1 1.2Study 2

Groups of 4 Sprague-Dawley rats each were weekly injected subcutaneouslywith 50 mg/kg of Ionis oligonucleotide for 6 weeks (total 7 doses). Therats were euthanized; and organs, urine and plasma were harvested forfurther analysis 1 day after the last dose.

Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver and kidneyfunction, plasma levels of alanine aminotransferase (ALT), aspartateaminotransferase (AST), blood urea nitrogen (BUN) and total bilirubin(TBIL) were measured using an automated clinical chemistry analyzer(Hitachi Olympus AU400c, Melville, N.Y.). The results are presented inthe table below. Modified oligonucleotides that caused changes in thelevels of any of the liver or kidney function markers outside theexpected range for modified oligonucleotides were excluded in furtherstudies.

TABLE 101 Plasma chemistry markers in Sprague-Dawley rats Compound ALTAST BUN TBIL Number (IU/L) (IU/L) (mg/dL) (mg/dL) PBS 70 66 15 0.121304884 70 85 19 0.11 1304890 49 78 18 0.11 1304906 77 103 18 0.15

Blood obtained from rat groups at the end of the study, day 43, weresent to IDEXX BioAnalytics for measurement of blood cell counts. Countstaken red blood cell (RBC) count, Hemoglobin (HGB), Hematocrit (HCT),platelet count (PLT), total white blood cell count (WBC), neutrophilcounts (NEU), lymphocyte counts (LYM), and monocyte counts (MON). Theresults are presented in the tables below. Ionis oligonucleotides thatcaused changes in the blood cell count outside the expected range formodified oligonucleotides were excluded in further studies.

TABLE 102 Blood Cell Count in Sprague-Dawley Rats Compound RBC HGB HCTPLT WBC NEU LYM MON No. (×106/μL) (g/dL) (%) (10³/μL) (×10³/μL) (%) (%)(%) PBS 7 14 39 351 8 13 81 5 1E+06 7 14 39 450 11 17 79 4 1E+06 8 14 40578 8 7 86 6 1E+06 8 15 41 545 10 15 78 7

To evaluate the effect of Ionis oligonucleotides on kidney function,urinary levels of micro total protein (MTP) and creatinine were measuredusing an automated clinical chemistry analyzer (Hitachi Olympus AU400c,Melville, N.Y.). The ratios of MTP to creatinine (MTP/C ratio) arepresented in the table below. Ionis oligonucleotides that caused changesin the levels of the ratio outside the expected range for modifiedoligonucleotides were excluded in further studies.

TABLE 103 MTP to creatinine ratio in Sprague-Dawley rats Compound NumberMTP/C PBS 3 1304884 15 1304890 16 1304906 12

Body weights of rats were measured at days 1 and 38 and the average bodyweight for each group is presented in the table below. Liver, spleen andkidney weights were measured at the end of the study, and are presentedin the table below. Ionis oligonucleotides that caused any changes inorgan weights outside the expected range for modified oligonucleotideswere excluded from further studies.

TABLE 104 Body and organ weights (g) Compound Body Weight Liver KidneySpleen Number (g) (g) (g) (g) PBS 474 17.4 3.7 0.8 1E+06 385 15.5 3.31.9 1E+06 385 15 3.4 1.5 1E+06 404 15.1 3.4 2.1

What is claimed:
 1. A modified oligonucleotide according to thefollowing chemical structure:

or a salt thereof.
 2. The modified oligonucleotide of claim 1, whereinthe modified oligonucleotide is the sodium salt or the potassium salt.3. A modified oligonucleotide according to the following chemicalstructure:


4. A composition, comprising the modified oligonucleotide of claim 1 anda pharmaceutically acceptable diluent or carrier.
 5. A composition,comprising the modified oligonucleotide of claim 1 and water.
 6. Acomposition, comprising the modified oligonucleotide of claim 3 and apharmaceutically acceptable diluent or carrier.
 7. A composition,comprising the modified oligonucleotide of claim 3 and water.
 8. Anoligomeric compound comprising a modified oligonucleotide according tothe following formula: ^(m)C_(ks)^(m)C_(ks)T_(ks)T_(ds)A_(ds)G_(ds)T_(ds)T_(ds)G_(ds)G_(ds)^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ks)A_(ks)A_(k) (SEQ ID NO: 6); wherein,A=an adenine nucleobase, ^(m)C=a 5-methyl cytosine nucleobase, G=aguanine nucleobase, T=a thymine nucleobase, k=a cEt modified sugarmoiety, d=β-D-2′-deoxyribonucleoside, and s=a phosphorothioateinternucleoside linkage.